Journal articles: 'Receptor MET'

1

Faoro, Leonardo, Gustavo M. Cervantes, Essam El-Hashani, and Ravi Salgia. "MET Receptor Tyrosine Kinase." Journal of Thoracic Oncology 4, no. 11 (November 2009): S1064—S1065. http://dx.doi.org/10.1097/01.jto.0000361752.86918.09.

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Safaie Qamsari, Elmira, Sepideh Safaei Ghaderi, Bahareh Zarei, Ruhollah Dorostkar, Salman Bagheri, Farhad Jadidi-Niaragh, Mohammad Hossein Somi, and Mehdi Yousefi. "The c-Met receptor: Implication for targeted therapies in colorectal cancer." Tumor Biology 39, no. 5 (May 2017): 101042831769911. http://dx.doi.org/10.1177/1010428317699118.

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c-Met (mesenchymal–epithelial transition factor) is a tyrosine kinase receptor activated by hepatocyte growth factor and regulates multiple biological processes, such as cell scattering, survival, and proliferation. Aberrant c-Met signaling has been implicated in a variety of cancer types, including colorectal cancer. c-Met is genetically altered through various mechanisms that is associated with colorectal cancer progression and metastasis. Especially, in colorectal cancer, preclinical evidence for the aberrant activation of the c-Met signaling exists. Accordingly, molecular targeting of c-Met receptor could be a promising strategy, in the treatment of colorectal cancer patients. Recently, it was also shown that crosstalk between c-Met and other cell surface receptors attributes to tumorigenesis and development of therapeutic resistance. Characterization of the molecular mechanisms through which c-Met crosstalks with other receptors in favor of tumor formation and progression remains to explore. This review will describe the mechanisms of aberrant c-Met signaling in colorectal cancer and discuss on additional roles for c-Met receptor through crosstalk with other tyrosine kinase receptors and cell surface proteins in colorectal cancer. Novel therapeutic approaches for c-Met pathway targeting will also be discussed.

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3

Clague, M. J. "Met Receptor: A Moving Target." Science Signaling 4, no. 190 (September 6, 2011): pe40. http://dx.doi.org/10.1126/scisignal.2002422.

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4

Lai, Andrea Z., Jasmine V. Abella, and Morag Park. "Crosstalk in Met receptor oncogenesis." Trends in Cell Biology 19, no. 10 (October 2009): 542–51. http://dx.doi.org/10.1016/j.tcb.2009.07.002.

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5

Carter, Stephanie, Sylvie Urbé, and Michael J. Clague. "The Met Receptor Degradation Pathway." Journal of Biological Chemistry 279, no. 51 (October 5, 2004): 52835–39. http://dx.doi.org/10.1074/jbc.m407769200.

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6

Goldoni, Silvia, Ashley Humphries, Alexander Nyström, Sampurna Sattar, Rick T. Owens, David J. McQuillan, Keith Ireton, and Renato V. Iozzo. "Decorin is a novel antagonistic ligand of the Met receptor." Journal of Cell Biology 185, no. 4 (May 11, 2009): 743–54. http://dx.doi.org/10.1083/jcb.200901129.

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Decorin, a member of the small leucine-rich proteoglycan gene family, impedes tumor cell growth by down-regulating the epidermal growth factor receptor. Decorin has a complex binding repertoire, thus, we predicted that decorin would modulate the bioactivity of other tyrosine kinase receptors. We discovered that decorin binds directly and with high affinity (Kd = ∼1.5 nM) to Met, the receptor for hepatocyte growth factor (HGF). Binding of decorin to Met is efficiently displaced by HGF and less efficiently by internalin B, a bacterial Met ligand. Interaction of decorin with Met induces transient receptor activation, recruitment of the E3 ubiquitin ligase c-Cbl, and rapid intracellular degradation of Met (half-life = ∼6 min). Decorin suppresses intracellular levels of β-catenin, a known downstream Met effector, and inhibits Met-mediated cell migration and growth. Thus, by antagonistically targeting multiple tyrosine kinase receptors, decorin contributes to reduction in primary tumor growth and metastastic spreading.

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7

Bolanos-Garcia, Victor Martin. "MET meet adaptors: Functional and structural implications in downstream signalling mediated by the Met receptor." Molecular and Cellular Biochemistry 276, no. 1-2 (August 2005): 149–57. http://dx.doi.org/10.1007/s11010-005-3696-6.

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8

Sachs, M., K. M. Weidner, V. Brinkmann, I. Walther, A. Obermeier, A. Ullrich, and W. Birchmeier. "Motogenic and morphogenic activity of epithelial receptor tyrosine kinases." Journal of Cell Biology 133, no. 5 (June 1, 1996): 1095–107. http://dx.doi.org/10.1083/jcb.133.5.1095.

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Receptor tyrosine kinases play essential roles in morphogenesis and differentiation of epithelia. Here we examined various tyrosine kinase receptors, which are preferentially expressed in epithelia (c-met, c-ros, c-neu, and the keratin growth factor [KGF] receptor), for their capacity to induce cell motility and branching morphogenesis of epithelial cells. We exchanged the ligand-binding domain of these receptors by the ectodomain of trkA and could thus control signaling by the new ligand, NGF. We demonstrate here that the tyrosine kinases of c-met, c-ros, c-neu, the KGF receptor, and trkA, but not the insulin receptor, induced scattering and increased motility of kidney epithelial cells in tissue culture. Mutational analysis suggests that SHC binding is essential for scattering and increased cell motility induced by trkA. The induction of motility in epithelial cells is thus an important feature of various receptor tyrosine kinases, which in vivo play a role in embryogenesis and metastasis. In contrast, only the c-met receptor promoted branching morphogenesis of kidney epithelial cells in three-dimensional matrices, which resemble the formation of tubular epithelia in development. Interestingly, the ability of c-met to induce morphogenesis could be transferred to trkA, when in a novel receptor hybrid COOH-terminal sequences of c-met (including Y14 to Y16) were fused to the trkA kinase domain. These data demonstrate that tubulogenesis of epithelia is a restricted activity of tyrosine kinases, as yet only demonstrated for the c-met receptor. We predict the existence of specific substrates that mediate this morphogenesis signal.

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9

Short, Ben. "Decorin has Met a new receptor." Journal of Cell Biology 185, no. 4 (May 11, 2009): 566. http://dx.doi.org/10.1083/jcb.1854iti3.

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10

Niemann, Hartmut H. "Structural insights into Met receptor activation." European Journal of Cell Biology 90, no. 11 (November 2011): 972–81. http://dx.doi.org/10.1016/j.ejcb.2010.11.014.

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11

Thayaparan, Thivyan, James F. Spicer, and John Maher. "The role of the HGF/Met axis in mesothelioma." Biochemical Society Transactions 44, no. 2 (April 11, 2016): 363–70. http://dx.doi.org/10.1042/bst20150252.

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Malignant mesothelioma is an asbestos-related cancer that occurs most commonly in the pleural space and is incurable. Increasing evidence suggests that aberrant receptor tyrosine kinase (RTK)-directed signalling plays a key role in the pathogenesis of this cancer. In the majority of mesotheliomas, up-regulated expression or signalling by Met, the receptor for hepatocyte growth factor (HGF) can be demonstrated. Following binding of ligand, Met relays signals that promote cell survival, proliferation, movement, invasiveness, branching morphogenesis and angiogenesis. Here we describe the HGF/Met axis and review the mechanisms that lead to the aberrant activation of this signalling system in mesothelioma. We also describe the cross-talk that occurs between HGF/Met and a number of other receptors, ligands and co-receptor systems. The prevalent occurrence of HGF/Met dysregulation in patients with mesothelioma sets the scene for the investigation of pharmaceutical inhibitors of this axis. In light of the inter-relationship between HGF/Met and other ligand receptor, combinatorial targeting strategies may provide opportunities for therapeutic advancement in this challenging tumour.

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12

Cossart, Pascale. "Met, the HGF–SF receptor: another receptor for Listeria monocytogenes." Trends in Microbiology 9, no. 3 (March 2001): 105–7. http://dx.doi.org/10.1016/s0966-842x(00)01943-0.

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13

Ma, P. C., S. Jiang, R. Du, S. Dietrich, Z. Tang, and J. A. Kern. "Modeling targeted inhibition of wild type and mutated c-MET receptor." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14010. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14010.

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14010 Background: c-MET belongs to the semaphorin superfamily of signaling proteins, containing three protein families (semaphorins, plexins, c-MET and RON) that have central roles in cell signaling. The c-MET receptor tyrosine kinase is involved in regulating cell growth/proliferation, survival, angiogenesis, cell scattering, cell motility and migration. Mutations in c-MET have been identified in various human cancers including lung cancer and papillary renal cell carcinomas. c-MET mutations occur within the extracellular seven-blade β-propeller fold sema domain (E168D, L229F, S325G, N375S), juxtamembrane domain (R988C, T1010I), and kinase domain (M1268T). We hypothesized that these mutations would have differential effects on the kinase inhibition. Methods: We modeled the various c-MET mutations from different functional domains of the receptor using a G418-resistant stable Cos-7 transfection cell system to determine their effect on sensitivity to a selective c-MET kinase inhibitor SU11274. Sensitivity to SU11274 inhibition was assayed by phospho-immunoblotting using phospho- specific antibody against the major tyrosine kinase phosphorylation epitopes pY1234/1235 of the c-MET kinase in vitro. Results: First, we identified that mutations in the sema and juxtamembrane domain were activating as defined by ligand-independent constitutive receptor activation. SU11274 was capable of inhibiting ligand induced signaling through the wild-type c-MET as well as mutant c-MET receptors harboring mutations in the sema, juxtamembrane and tyrosine kinase domain. However, SU11274 inhibition of mutant c-MET was mutation-dependent, with the juxtamembrane domain mutations R988C and T1010I resulting in a receptor form that was less sensitive to SU11274. Mutations in the sema and kinase domain also resulted in varying sensitivity to inhibition by SU11274 inhibition. Conclusions: Mutations in the sema and juxtamembrane domain of c-MET result in receptor activation. The small molecule inhibitor SU11274 is active against wild type and mutated c- MET receptor. Further studies to characterize the signaling effects and the mechanism of sensitivity and resistance of c-MET mutations to specific inhibitors are crucial in the successful development of therapeutic c-MET and mutant c-MET inhibitors. No significant financial relationships to disclose.

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Shattuck, David L., Jamie K. Miller, Melanie Laederich, Melanie Funes, Heidi Petersen, Kermit L. Carraway, and Colleen Sweeney. "LRIG1 Is a Novel Negative Regulator of the Met Receptor and Opposes Met and Her2 Synergy." Molecular and Cellular Biology 27, no. 5 (December 18, 2006): 1934–46. http://dx.doi.org/10.1128/mcb.00757-06.

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ABSTRACT The Met receptor tyrosine kinase regulates a complex array of cellular behaviors collectively known as “invasive growth.” While essential for normal development and wound repair, this program is frequently co-opted by tumors to promote their own growth, motility, and invasion. Met is overexpressed in a variety of human tumors, and this aberrant expression correlates with poor patient prognosis. Previous studies indicate that Met receptor levels are governed in part by cbl-mediated ubiquitination and degradation, and uncoupling of Met from cbl-mediated ubiquitination promotes its transforming activity. Here we describe a novel mechanism for Met degradation. We find that the Met receptor interacts with the transmembrane protein LRIG1 independent of hepatocyte growth factor (HGF) stimulation and that LRIG1 destabilizes the Met receptor in a cbl-independent manner. Overexpression of LRIG1 destabilizes endogenous Met receptor in breast cancer cells and impairs their ability to respond to HGF. LRIG1 knockdown increases Met receptor half-life, indicating that it plays an essential role in Met degradation. Finally, LRIG1 opposes Met synergy with the ErbB2/Her2 receptor tyrosine kinase in driving cellular invasion. We conclude that LRIG1 is a novel suppressor of Met function, serving to regulate cellular receptor levels by promoting Met degradation in a ligand- and cbl-independent manner.

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15

Gras, J. "Savolitinib. Hepatocyte growth factor receptor (HGFR, MET, c-Met) inhibitor, Cancer therapy." Drugs of the Future 43, no. 1 (2018): 5. http://dx.doi.org/10.1358/dof.2018.043.01.2754012.

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16

Flynn, Francis W., Thomas R. Kirchner, and Margaret E. Clinton. "Brain vasopressin and sodium appetite." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 282, no. 4 (April 1, 2002): R1236—R1244. http://dx.doi.org/10.1152/ajpregu.00181.2001.

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Intraventricular injections of vasopressin (VP) and antagonists with varying degrees of specificity for the VP receptors were used to identify the action of endogenous brain VP on 0.3 M NaCl intake by sodium-deficient rats. Lateral ventricular injections of 100 ng and 1 μg VP caused barrel rotations and a dramatic decrease in NaCl intake by sodium-deficient rats and suppressed sucrose intake. Intraventricular injection of the V1/V2 receptor antagonist [d(CH2)5 1,O-Et-Tyr2,Val4, Arg8]VP and the V1 receptor antagonist [d(CH2)5 1,O-Me-Tyr2,Arg8]VP (MeT-AVP) significantly suppressed NaCl intake by sodium-deficient rats without causing motor disturbances. MeT-AVP had no effect on sucrose intake (0.1 M). In contrast, the selective V2 receptor antagonist had no significant effect on NaCl intake. Last, injections of 100 ng MeT-AVP decreased mean arterial blood pressure (MAP), whereas 100 ng VP elevated MAP and pretreatment with MeT-AVP blocked the pressor effect of VP. These results indicate that the effects produced by 100 ng MeT-AVP represent receptor antagonistic activity. These findings suggest that the effect of exogenous VP on salt intake is secondary to motor disruptions and that endogenous brain VP neurotransmission acting at V1 receptors plays a role in the arousal of salt appetite.

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17

Mukohara, Toru, Gabriel Civiello, Ian J. Davis, Michele L. Taffaro, James Christensen, David E. Fisher, Bruce E. Johnson, and Pasi A. Jänne. "Inhibition of the Met Receptor in Mesothelioma." Clinical Cancer Research 11, no. 22 (November 15, 2005): 8122–30. http://dx.doi.org/10.1158/1078-0432.ccr-05-1191.

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18

Fan, Steven Hung-Yi, Yuka Numata, and Masayuki Numata. "Endosomal Na+/H+ exchanger NHE5 influences MET recycling and cell migration." Molecular Biology of the Cell 27, no. 4 (February 15, 2016): 702–15. http://dx.doi.org/10.1091/mbc.e15-04-0257.

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Increased recycling and elevated cell surface expression of receptors serve as a mechanism for persistent receptor-mediated signaling. We show that the neuron-enriched Na+/H+ exchanger NHE5 is abundantly expressed in C6 glioma cells and plays an important part in regulating cell surface expression of the receptor tyrosine kinases MET and EGF receptor. NHE5 is associated with transferrin receptor (TfR)- and Rab11-positive recycling endosomal membranes, and NHE5 knockdown by short hairpin RNA significantly elevates pH of TfR-positive recycling endosomes. We present evidence that NHE5 facilitates MET recycling to the plasma membrane, protects MET from degradation, and modulates HGF-induced phosphatidylinositol-3-kinase and mitogen-activated protein kinase signaling. Moreover, NHE5 depletion abrogates Rac1 and Cdc42 signaling and actin cytoskeletal remodeling. We further show that NHE5 knockdown impairs directed cell migration and causes loss of cell polarity. Our study highlights a possible role of recycling endosomal pH in regulating receptor-mediated signaling through vesicular trafficking.

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19

Harwardt, Marie-Lena I. E., Mark S. Schröder, Yunqing Li, Sebastian Malkusch, Petra Freund, Shashi Gupta, Nebojsa Janjic, et al. "Single-Molecule Super-Resolution Microscopy Reveals Heteromeric Complexes of MET and EGFR upon Ligand Activation." International Journal of Molecular Sciences 21, no. 8 (April 17, 2020): 2803. http://dx.doi.org/10.3390/ijms21082803.

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Receptor tyrosine kinases (RTKs) orchestrate cell motility and differentiation. Deregulated RTKs may promote cancer and are prime targets for specific inhibitors. Increasing evidence indicates that resistance to inhibitor treatment involves receptor cross-interactions circumventing inhibition of one RTK by activating alternative signaling pathways. Here, we used single-molecule super-resolution microscopy to simultaneously visualize single MET and epidermal growth factor receptor (EGFR) clusters in two cancer cell lines, HeLa and BT-20, in fixed and living cells. We found heteromeric receptor clusters of EGFR and MET in both cell types, promoted by ligand activation. Single-protein tracking experiments in living cells revealed that both MET and EGFR respond to their cognate as well as non-cognate ligands by slower diffusion. In summary, for the first time, we present static as well as dynamic evidence of the presence of heteromeric clusters of MET and EGFR on the cell membrane that correlates with the relative surface expression levels of the two receptors.

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20

Ayoub, Nehad M., Rami J. Yaghan, Alia H. Al-Mohtaseb, Najla Aldaoud, Ismail I. Matalka, and Muwada E. Elhassan. "Expression of Insulin Receptor and c-MET Is Associated with Clinicopathologic Characteristics and Molecular Subtypes in Premenopausal Breast Cancer Patients." Applied Sciences 10, no. 5 (February 29, 2020): 1614. http://dx.doi.org/10.3390/app10051614.

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Receptor Tyrosine Kinases (RTKs) represent a class of transmembrane receptors known to play an important role in cancer development and progression. In this study, the expression of insulin receptor (IR) and the hepatocyte growth factor receptor (c-MET) was examined in breast cancer patients. Immunohistochemistry for IR and c-MET was performed on 71 cases of invasive breast cancer and expression scores were correlated with clinicopathologic characteristics and molecular subtypes and further stratified based on a menopausal status. Expression of IR was significantly associated with the tumor grade (p = 0.017) and estrogen receptor (ER) expression (p = 0.015). There was a significant positive correlation between IR and c-MET expression scores (rho = 0.458, p < 0.001). Among premenopausal cases, IR scores were significantly higher in patients with grade I/II disease (p = 0.025), ER-positive (p = 0.030), and progesterone receptor (PR)-positive carcinoma (p = 0.015). c-MET expression scores were significantly higher among premenopausal patients with ER-positive (p = 0.007) and PR-positive carcinoma (p = 0.024). IR expression scores were significantly different among molecular subtypes for all patients (p = 0.006) and among premenopausal cases (p = 0.035). c-MET expression was statistically different among molecular subtypes for premenopausal patients (p = 0.019). Survival analysis revealed that the expression status of IR and c-MET was not associated with overall survival. Our findings support a favorable prognostic value for IR and c-MET expression in premenopausal breast cancer patients.

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21

Mood, Kathleen, Caroline Saucier, Yong-Sik Bong, Hyun-Shik Lee, Morag Park, and Ira O. Daar. "Gab1 Is Required for Cell Cycle Transition, Cell Proliferation, and Transformation Induced by an Oncogenic Met Receptor." Molecular Biology of the Cell 17, no. 9 (September 2006): 3717–28. http://dx.doi.org/10.1091/mbc.e06-03-0244.

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We have shown previously that either Grb2- or Shc-mediated signaling from the oncogenic Met receptor Tpr-Met is sufficient to trigger cell cycle progression in Xenopus oocytes. However, direct binding of these adaptors to Tpr-Met is dispensable, implying that another Met binding partner mediates these responses. In this study, we show that overexpression of Grb2-associated binder 1 (Gab1) promotes cell cycle progression when Tpr-Met is expressed at suboptimal levels. This response requires that Gab1 possess an intact Met-binding motif, the pleckstrin homology domain, and the binding sites for phosphatidylinositol 3-kinase and tyrosine phosphatase SHP-2, but not the Grb2 and CrkII/phospholipase Cγ binding sites. Importantly, we establish that Gab1-mediated signals are critical for cell cycle transition promoted by the oncogenic Met and fibroblast growth factor receptors, but not by progesterone, the natural inducer of cell cycle transition in Xenopus oocytes. Moreover, Gab1 is essential for Tpr-Met–mediated morphological transformation and proliferation of fibroblasts. This study provides the first evidence that Gab1 is a key binding partner of the Met receptor for induction of cell cycle progression, proliferation, and oncogenic morphological transformation. This study identifies Gab1 and its associated signaling partners as potential therapeutic targets to impair proliferation or transformation of cancer cells in human malignancies harboring a deregulated Met receptor.

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22

Tulasne, David, Réjane Paumelle, K. Michael Weidner, Bernard Vandenbunder, and Véronique Fafeur. "The Multisubstrate Docking Site of the MET Receptor Is Dispensable for MET-mediated RAS Signaling and Cell Scattering." Molecular Biology of the Cell 10, no. 3 (March 1999): 551–65. http://dx.doi.org/10.1091/mbc.10.3.551.

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The scatter factor/hepatocyte growth factor regulates scattering and morphogenesis of epithelial cells through activation of the MET tyrosine kinase receptor. In particular, the noncatalytic C-terminal tail of MET contains two autophosphorylation tyrosine residues, which form a multisubstrate-binding site for several cytoplasmic effectors and are thought to be essential for signal transduction. We show here that a MET receptor mutated on the four C-terminal tyrosine residues, Y1311F, Y1347F, Y1354F, and Y1363F, can induce efficiently a transcriptional response and cell scattering, whereas it cannot induce cell morphogenesis. Although the mutated receptor had lost its ability to recruit and/or activate known signaling molecules, such as GRB2, SHC, GAB1, and PI3K, by using a sensitive association–kinase assay we found that the mutated receptor can still associate and phosphorylate a ∼250-kDa protein. By further examining signal transduction mediated by the mutated MET receptor, we established that it can transmit efficient RAS signaling and that cell scattering by the mutated MET receptor could be inhibited by a pharmacological inhibitor of the MEK-ERK (MAP kinase kinase–extracellular signal-regulated kinase) pathway. We propose that signal transduction by autophosphorylation of the C-terminal tyrosine residues is not the sole mechanism by which the activated MET receptor can transmit RAS signaling and cell scattering.

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23

Kamikura, Darren M., Hanane Khoury, Christiane Maroun, Monica A. Naujokas, and Morag Park. "Enhanced Transformation by a Plasma Membrane-Associated Met Oncoprotein: Activation of a Phosphoinositide 3′-Kinase-Dependent Autocrine Loop Involving Hyaluronic Acid and CD44." Molecular and Cellular Biology 20, no. 10 (May 15, 2000): 3482–96. http://dx.doi.org/10.1128/mcb.20.10.3482-3496.2000.

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ABSTRACT A Met-hepatocyte growth factor receptor oncoprotein, Tpr-Met, generated by chromosomal rearrangement, fuses a protein dimerization motif with the cytoplasmic domain of the Met receptor, producing a cytosolic, constitutively activated tyrosine kinase. Although both the Met receptor and the Tpr-Met oncoprotein associate with the same substrates, activating mutations of the Met receptor in hereditary papillary renal carcinomas have different signaling requirements for transformation than Tpr-Met. This suggests differential activation of membrane-localized pathways by oncogenic forms of the membrane-bound Met receptor but not by the cytoplasmic Tpr-Met oncoprotein. To establish which pathways might be differentially regulated, we have localized the constitutively activated Tpr-Met oncoprotein to the membrane using the c-src myristoylation signal. Membrane localization enhances cellular transformation, focus formation, and anchorage-independent growth and induces tumors with a distinct myxoid phenotype. This correlates with the induction of hyaluronic acid (HA) and the presence of a distinct form of its receptor, CD44. A pharmacological inhibitor of phosphoinositide 3′ kinase (PI3′K), inhibits the production of HA, and conversely, an activated, plasma membrane-targeted form of PI3′K is sufficient to enhance HA production. Furthermore, the multisubstrate adapter protein Gab-1, which couples the Met receptor with PI3′K, enhances Met receptor-dependent HA synthesis in a PI3′K-dependent manner. These results provide a positive link to a role for HA and CD44 in Met receptor-mediated oncogenesis and implicate PI3′K in these events.

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Rodrigues, G. A., M. A. Naujokas, and M. Park. "Alternative splicing generates isoforms of the met receptor tyrosine kinase which undergo differential processing." Molecular and Cellular Biology 11, no. 6 (June 1991): 2962–70. http://dx.doi.org/10.1128/mcb.11.6.2962.

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The met proto-oncogene is a member of the family of tyrosine kinase growth factor receptors. We describe the isolation and characterization of a cDNA clone (pOK) for the met receptor from a gastric carcinoma cell line. This clone differs from the published cDNA clone by the absence of 54 bp predicted to encode 18 amino acids in the extracellular domain. The pOK cDNA corresponds to the most abundant met RNA species of 8 kb expressed in human cell lines and tissue, and we show that there are in fact two 8-kb met receptor tyrosine kinase (RTK) isoforms that are generated by alternative splicing. This newly described met isoform when transiently expressed in COS cells encodes a protein of 190 kDa which corresponds in size to the p190 met alpha beta heterodimer expressed in human cell lines. Furthermore, we show that the 190-kDa product of pOK consists of the 140-kDa met beta subunit associated with the 50-kDa met alpha subunit. This finding suggests that both the alpha and beta met chains are encoded by this construct and confirms the hypothesis that a single chain precursor is cleaved to produce both subunits of met. In contrast, the previously characterized met isoform corresponds to a minor met RNA species and encodes a protein of 170 kDa that is not cleaved yet is processed in a manner that allows cell surface expression. Both met RTK isoforms are autophosphorylated in the in vitro kinase assay. These results suggest that different isoforms of the met RTK may have distinct biological activities.

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Rodrigues, G. A., M. A. Naujokas, and M. Park. "Alternative splicing generates isoforms of the met receptor tyrosine kinase which undergo differential processing." Molecular and Cellular Biology 11, no. 6 (June 1991): 2962–70. http://dx.doi.org/10.1128/mcb.11.6.2962-2970.1991.

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The met proto-oncogene is a member of the family of tyrosine kinase growth factor receptors. We describe the isolation and characterization of a cDNA clone (pOK) for the met receptor from a gastric carcinoma cell line. This clone differs from the published cDNA clone by the absence of 54 bp predicted to encode 18 amino acids in the extracellular domain. The pOK cDNA corresponds to the most abundant met RNA species of 8 kb expressed in human cell lines and tissue, and we show that there are in fact two 8-kb met receptor tyrosine kinase (RTK) isoforms that are generated by alternative splicing. This newly described met isoform when transiently expressed in COS cells encodes a protein of 190 kDa which corresponds in size to the p190 met alpha beta heterodimer expressed in human cell lines. Furthermore, we show that the 190-kDa product of pOK consists of the 140-kDa met beta subunit associated with the 50-kDa met alpha subunit. This finding suggests that both the alpha and beta met chains are encoded by this construct and confirms the hypothesis that a single chain precursor is cleaved to produce both subunits of met. In contrast, the previously characterized met isoform corresponds to a minor met RNA species and encodes a protein of 170 kDa that is not cleaved yet is processed in a manner that allows cell surface expression. Both met RTK isoforms are autophosphorylated in the in vitro kinase assay. These results suggest that different isoforms of the met RTK may have distinct biological activities.

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Hammond, Dean E., Stephanie Carter, John McCullough, Sylvie Urbé, George Vande Woude, and Michael J. Clague. "Endosomal Dynamics of Met Determine Signaling Output." Molecular Biology of the Cell 14, no. 4 (April 2003): 1346–54. http://dx.doi.org/10.1091/mbc.e02-09-0578.

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Proteasomal activity is required for Met receptor degradation after acute stimulation with hepatocyte growth factor (HGF). Inhibition of proteasomal activity with lactacystin leads to a block in the endocytic trafficking of Met such that the receptor fails to reach late endosomes/lysosomes, where degradation by acid-dependent proteases takes place ( Hammond et al., 2001 ). In this article, we have biochemically determined Met internalization rates from the cell surface and shown that lactacystin does not inhibit the initial HGF-dependent internalization step of Met. Instead, it promotes the recycling pathway from early endosomes at the expense of sorting to late endosomes, thereby ensuring rapid return of internalized Met to the cell surface. We have used this perturbation of Met endosomal sorting by lactacystin to examine the consequences for HGF-dependent signaling outputs. In control cells HGF-dependent receptor autophosphorylation reaches a maximal level over 5–10 min but then attenuates over the ensuing 50 min. Furthermore, Met dephosphorylation can be kinetically dissociated from Met degradation. In lactacystin-treated cells, we observe a failure of Met dephosphorylation as well as Met degradation. Elements of the mitogen-activated protein kinase cascade, downstream of receptor activation, show a normal kinetic profile of phosphorylation, indicating that the mitogen-activated protein kinase pathway can attenuate in the face of sustained receptor activation. The HGF-dependent phosphorylation of a receptor substrate that is localized to clathrin-coated regions of sorting endosomes, Hrs, is dramatically reduced by lactacystin treatment. Reduction of cellular Hrs levels by short interfering RNA modestly retards Met degradation and markedly prevents the attenuation of Met phosphorylation. HGF-dependent Hrs phosphorylation and Met dephosphorylation may provide signatures for retention of the receptor in coated regions of the endosome implicated in sorting to lysosomes.

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27

Mills, John S., Heini M. Miettinen, David Cummings, and Algirdas J. Jesaitis. "Characterization of the Binding Site on the Formyl Peptide Receptor Using Three Receptor Mutants and Analogs of Met-Leu-Phe and Met-Met-Trp-Leu-Leu." Journal of Biological Chemistry 275, no. 50 (August 25, 2000): 39012–17. http://dx.doi.org/10.1074/jbc.m003081200.

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28

Simiczyjew, Aleksandra, Ewelina Dratkiewicz, Marleen Van Troys, Christophe Ampe, Ilona Styczeń, and Dorota Nowak. "Combination of EGFR Inhibitor Lapatinib and MET Inhibitor Foretinib Inhibits Migration of Triple Negative Breast Cancer Cell Lines." Cancers 10, no. 9 (September 17, 2018): 335. http://dx.doi.org/10.3390/cancers10090335.

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Triple-negative breast cancer (TNBC) is the most challenging subtype to treat due to the lack of estrogen receptor, progesterone receptor, and HER2 expression, which excludes the usage of directed targeted therapy against them. Promising therapeutic targets are the hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR), which expression is frequently elevated in TNBC. Inhibitors of these receptors used as monotherapy are often ineffective. Due to that, we studied the efficacy of combined therapy targeting MET and EGFR simultaneously. Two TNBC cell lines were treated with lapatinib (a dual EGFR and HER2 inhibitor), foretinib (a MET inhibitor), or a combination of the two. After the inhibitors treatment, we verified the cell viability (XTT assay), distribution of the cell cycle phases, the activation of signaling pathways (Western blotting), distribution of invadopodia, fluorescent gelatin digestion (immunofluorescence), and the invasion capacity of cells. A combination of foretinib and lapatinib effectively reduced the viability of examined cells, led to G2/M arrest and reduction of pAKT. There was also a decreasein number of invadopodia formed by cells, their ability to digest gelatin and reduction of cells migration/invasion capacity. Therapy targeting of both EGFR and MET receptors was much more effective against tested cells than monotherapy. We selected a combination of drugs that could be successfully used against this breast cancer subtype.

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Szewczyk, Barbara, Klaudia Skrzypek, and Marcin Majka. "Targeting MET Receptor in Rhabdomyosarcoma: Rationale and Progress." Current Drug Targets 18, no. 1 (December 2, 2016): 98–107. http://dx.doi.org/10.2174/1389450117666151209124123.

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Goldoni, Silvia, Ashley Humphries, Rick T. Owens, David J. McQuillan, and Renato V. Iozzo. "Decorin binds to and downregulates the MET receptor." Matrix Biology 27 (December 2008): 12–13. http://dx.doi.org/10.1016/j.matbio.2008.09.230.

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Bardelli, Alberto, Luisa Pugliese, and Paolo M. Comoglio. "“Invasive-growth” signaling by the Met/HGF receptor." Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1333, no. 3 (December 1997): M41—M51. http://dx.doi.org/10.1016/s0304-419x(97)00026-7.

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Giordano, S., M. F. di Renzo, M. Olivero, A. Mondino, Z. Zhen, E. Medico, and P. M. Comoglio. "The c-met/HGF receptor in human tumours." European Journal of Cancer Prevention 1 (October 1992): 45–50. http://dx.doi.org/10.1097/00008469-199210003-00007.

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Ponzetto, Carola, Zhu Zhen, Enrica Audero, Flavio Maina, Alberto Bardelli, M. Lisa Basile, Silvia Giordano, Radha Narsimhan, and Paolo Comoglio. "Specific Uncoupling of GRB2 from the Met Receptor." Journal of Biological Chemistry 271, no. 24 (June 14, 1996): 14119–23. http://dx.doi.org/10.1074/jbc.271.24.14119.

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Tsarfaty, I., J. Resau, S. Rulong, I. Keydar, D. Faletto, and G. Vande Woude. "The met proto-oncogene receptor and lumen formation." Science 257, no. 5074 (August 28, 1992): 1258–61. http://dx.doi.org/10.1126/science.1387731.

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Jeffers, M., G. A. Taylor, K. M. Weidner, S. Omura, and G. F. Vande Woude. "Degradation of the Met tyrosine kinase receptor by the ubiquitin-proteasome pathway." Molecular and Cellular Biology 17, no. 2 (February 1997): 799–808. http://dx.doi.org/10.1128/mcb.17.2.799.

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The Met tyrosine kinase receptor is a widely expressed molecule which mediates pleiotropic cellular responses following activation by its ligand, hepatocyte growth factor/scatter factor (HGF/SF). In this communication we demonstrate that significant Met degradation is induced by HGF/SF and that this degradation can be blocked by lactacystin, an inhibitor of proteasome activity. We also show that Met is rapidly polyubiquitinated in response to ligand and that polyubiquitinated Met molecules, which are normally unstable, are stabilized by lactacystin. Both HGF/SF-induced degradation and polyubiquitination of Met were shown to be dependent on the receptor possessing intact tyrosine kinase activity. Finally, we found that a normally highly labile 55-kDa fragment of the Met receptor is stabilized by lactacystin and demonstrate that it represents a cell-associated remnant that is generated following the ligand-independent proteolytic cleavage of the Met receptor in its extracellular domain. This truncated Met molecule encompasses the kinase domain of the receptor and is itself tyrosine phosphorylated. We conclude that the ubiquitin-proteasome pathway plays a significant role in the degradation of the Met tyrosine kinase receptor as directed by ligand-dependent and -independent signals. We propose that this proteolytic pathway may be important for averting cellular transformation by desensitizing Met signaling following ligand stimulation and by eliminating potentially oncogenic fragments generated via extracellular cleavage of the Met receptor.

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Leiser, Dominic, Benoît Pochon, Wieslawa Blank-Liss, Paola Francica, Astrid A. Glück, Daniel M. Aebersold, Yitzhak Zimmer, and Michaela Medová. "Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation." FEBS Letters 588, no. 5 (January 17, 2014): 653–58. http://dx.doi.org/10.1016/j.febslet.2013.12.025.

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Jenke, Robert, Miriam Holzhäuser-Rein, Stefanie Mueller-Wilke, Florian Lordick, Achim Aigner, and Thomas Büch. "SATB1-Mediated Upregulation of the Oncogenic Receptor Tyrosine Kinase HER3 Antagonizes MET Inhibition in Gastric Cancer Cells." International Journal of Molecular Sciences 22, no. 1 (December 23, 2020): 82. http://dx.doi.org/10.3390/ijms22010082.

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MET-amplified gastric cancer cells are extremely sensitive to MET inhibition in vitro, whereas clinical efficacy of MET inhibitors is disappointing. The compensatory activation of other oncogenic growth factor receptors may serve as an underlying mechanism of resistance. In this study, we analyzed the role of HER receptors, in particular HER3 and its ligand heregulin, in this respect. This also included the chromatin-organizer protein SATB1, as an established regulator of HER expression in other tumor entities. In a panel of MET-amplified gastric carcinoma cell lines, cell growth under anchorage-dependent and independent conditions was studied upon inhibitor treatment or siRNA-mediated knockdown. Expression analyses were performed using RT-qPCR, FACS, and immunoblots. Signal transduction was monitored via antibody arrays and immunoblots. As expected, MET inhibition led to a growth arrest and inhibition of MAPK signaling. Strikingly, however, this was accompanied by a rapid and profound upregulation of the oncogenic receptor HER3. This finding was determined as functionally relevant, since HER3 activation by HRG led to partial MET inhibitor resistance, and MAPK/Akt signaling was even found enhanced upon HRG+MET inhibitor treatment compared to HRG alone. SATB1 was identified as mediator of HER3 upregulation. Concomitantly, SATB1 knockdown prevented upregulation of HER3, thus abrogating the HRG-promoted rescue from MET inhibition. Taken together, our results introduce the combined HER3/MET inhibition as strategy to overcome resistance towards MET inhibitors.

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Abella, Jasmine V., Pascal Peschard, Monica A. Naujokas, Tong Lin, Caroline Saucier, Sylvie Urbé, and Morag Park. "Met/Hepatocyte Growth Factor Receptor Ubiquitination Suppresses Transformation and Is Required for Hrs Phosphorylation." Molecular and Cellular Biology 25, no. 21 (November 1, 2005): 9632–45. http://dx.doi.org/10.1128/mcb.25.21.9632-9645.2005.

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ABSTRACT The Met receptor tyrosine kinase (RTK) regulates epithelial remodeling, dispersal, and invasion and is deregulated in many human cancers. It is now accepted that impaired down-regulation, as well as sustained activation, of RTKs could contribute to their deregulation. Down-regulation of the Met receptor involves ligand-induced internalization, ubiquitination by Cbl ubiquitin ligases, and lysosomal degradation. Here we report that a ubiquitination-deficient Met receptor mutant (Y1003F) is tumorigenic in vivo. The Met Y1003F mutant is internalized, and undergoes endosomal trafficking with kinetics similar to the wild-type Met receptor, yet is inefficiently targeted for degradation. This results in sustained activation of Met Y1003F and downstream signals involving the Ras-mitogen-activated protein kinase pathway, cell transformation, and tumorigenesis. Although Met Y1003F undergoes endosomal trafficking and localizes with the cargo-sorting protein Hrs, it is unable to induce phosphorylation of Hrs. Fusion of monoubiquitin to Met Y1003F is sufficient to decrease Met receptor stability and prevent sustained MEK1/2 activation. In addition, this rescues Hrs tyrosine phosphorylation and decreases transformation in a focus-forming assay. These results demonstrate that Cbl-dependent ubiquitination is dispensable for Met internalization but is critical to target the Met receptor to components of the lysosomal sorting machinery and to suppress its inherent transforming activity.

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Sachs, Martin, Henning Brohmann, Dietmar Zechner, Thomas Müller, Jörg Hülsken, Ingrid Walther, Ute Schaeper, Carmen Birchmeier, and Walter Birchmeier. "Essential Role of Gab1 for Signaling by the C-Met Receptor in Vivo." Journal of Cell Biology 150, no. 6 (September 18, 2000): 1375–84. http://dx.doi.org/10.1083/jcb.150.6.1375.

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The docking protein Gab1 binds phosphorylated c-Met receptor tyrosine kinase directly and mediates signals of c-Met in cell culture. Gab1 is phosphorylated by c-Met and by other receptor and nonreceptor tyrosine kinases. Here, we report the functional analysis of Gab1 by targeted mutagenesis in the mouse, and compare the phenotypes of the Gab1 and c-Met mutations. Gab1 is essential for several steps in development: migration of myogenic precursor cells into the limb anlage is impaired in Gab1−/− embryos. As a consequence, extensor muscle groups of the forelimbs are virtually absent, and the flexor muscles reach less far. Fewer hindlimb muscles exist, which are smaller and disorganized. Muscles in the diaphragm, which also originate from migratory precursors, are missing. Moreover, Gab1−/− embryos die in a broad time window between E13.5 and E18.5, and display reduced liver size and placental defects. The labyrinth layer, but not the spongiotrophoblast layer, of the placenta is severely reduced, resulting in impaired communication between maternal and fetal circulation. Thus, extensive similarities between the phenotypes of c-Met and HGF/SF mutant mice exist, and the muscle migration phenotype is even more pronounced in Gab1−/−:c-Met+/− embryos. This is genetic evidence that Gab1 is essential for c-Met signaling in vivo. Analogy exists to signal transmission by insulin receptors, which require IRS1 and IRS2 as specific docking proteins.

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Stella, Giulia, Alessandra Corino, Giulia Berzero, Stefan Kolling, Andrea Filippi, and Silvia Benvenuti. "Brain Metastases from Lung Cancer: Is MET an Actionable Target?" Cancers 11, no. 3 (February 26, 2019): 271. http://dx.doi.org/10.3390/cancers11030271.

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The process of metastatic dissemination begins when malignant cells start to migrate and leave the primary mass. It is now known that neoplastic progression is associated with a combination of genetic and epigenetic events. Cancer is a genetic disease and this pathogenic concept is the basis for a new classification of tumours, based precisely on the presence of definite genetic lesions to which the clones are addicted. Regarding the scatter factor receptors MET and Recepteur d’Origin Nantais (RON), it is recognised that MET is an oncogene necessary for a narrow subset of tumours (MET-addicted) while it works as an adjuvant metastogene for many others. This notion highlights that the anti-MET therapy can be effective as the first line of intervention in only a few MET-addicted cases, while it is certainly more relevant to block MET in cases of advanced neoplasia that exploit the activation of the invasive growth program to promote dissemination in other body parts. Few data are instead related to the role played by RON, a receptor homologous to MET. We have already demonstrated an implication of MET and RON genes in brain metastases from lung cancer. On this basis, the aim of this work is to recapitulate and dissect the molecular basis of metastatic brain dissemination from lung cancer. The latter is among the big killers and frequently gives rise to brain metastases, most often discovered at diagnosis. Molecular mechanisms leading to tumour spread to the brain are mostly unknown and in turn these tragic cases are still lacking effective therapies. Based on previously published data from our group, we aim to summarise and analyse the pathogenic mechanisms leading to activation of the scatter factor receptor in brain metastatic lesions of lung primaries, from the point of view of replacing the currently used empirical treatment with a more targeted approach.

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RABKIN, RALPH, FERNANDO FERVENZA, TANNY TSAO, RICHARD SIBLEY, MICHAEL FRIEDLAENDER, FAY HSU, CHARLES LASSMAN, MICHAEL HAUSMANN, PHIL HUIE, and RALPH H. SCHWALL. "Hepatocyte Growth Factor Receptor in Acute Tubular Necrosis." Journal of the American Society of Nephrology 12, no. 3 (March 2001): 531–40. http://dx.doi.org/10.1681/asn.v123531.

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Abstract. In acute tubular necrosis, there are early transient increases in circulating and local bioactive hepatocyte growth factor (HGF) levels and renal HGF receptor (c-MET) gene expression. It has therefore been suggested that endogenous HGF may play a role in initiating renal repair. To test this hypothesis, changes in the levels, activity, and anatomic distribution of c-MET protein were characterized in relation to the onset and localization of DNA synthesis in kidneys of rats with ischemia-induced acute tubular necrosis. Whole-kidney c-MET protein levels were significantly increased in the injured kidneys 12 h after injury and rose to a maximum after 1 d, exceeding the control values by sevenfold. Eight days after injury, c-MET levels, although decreasing, were still elevated above control values. An increase in the levels of activated c-MET, i.e., tyrosine-phosphorylated c-MET, was also evident as early as 12 h after injury. Histologic analyses demonstrated that the increase in c-MET immunoreactivity was most marked in the most severely damaged nephron segments in the outer medulla. In injured proximal tubules, the receptor was redistributed from an apical location to an intracellular location. DNA synthesis was increased in the injured kidneys, especially in the outer medulla, where the increase in c-MET protein levels was most prominent. The increase in DNA synthesis was first detected 12 h after the initial increase in activated c-MET levels. It is concluded that the early increases in the levels of c-MET protein and activated receptor support the hypothesis that HGF participates in the initiation of renal regeneration. In addition, the persistent elevation of c-Met protein levels suggests that prolonged and even late treatment with HGF may be of therapeutic value

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Lee, Hyojin, Tae Hee Kim, Daechan Park, Mihue Jang, Justin J. Chung, Soo Hyun Kim, Sang-Heon Kim, Kwan Hyi Lee, Youngmee Jung, and Seung Ja Oh. "Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer Treatment." Pharmaceutics 12, no. 7 (July 21, 2020): 689. http://dx.doi.org/10.3390/pharmaceutics12070689.

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Membrane receptors overexpressed in diseased states are considered novel therapeutic targets. However, the single targeting approach faces several fundamental issues, such as poor efficacy, resistance, and toxicity. Here, we report a dual-targeting strategy to enhance anti-cancer efficacy via synergistic proximity interactions between therapeutics and two receptor proteins. Importantly, we report the first finding of an interaction between c-Met and nucleolin and demonstrate the therapeutic value of targeting the interaction between them. Bispecific nanocarriers densely grafted with anti-c-Met and -nucleolin aptamer increased the local concentration of aptamers at the target sites, in addition to inducing target receptor clustering. It was also demonstrated that the simultaneous targeting of c-Met and nucleolin inhibited the cellular functions of the receptors and increased anti-cancer efficacy by altering the cell cycle. Our findings pave the way for the development of an effective combinatorial treatment based on nanoconstruct-mediated interaction between receptors.

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Xu, Yiru, Wei Xia, Dustin Baker, Jin Zhou, Hyuk Chol Cha, John J. Voorhees, and Gary J. Fisher. "Receptor-type Protein Tyrosine Phosphatase β (RPTP-β) Directly Dephosphorylates and Regulates Hepatocyte Growth Factor Receptor (HGFR/Met) Function." Journal of Biological Chemistry 286, no. 18 (March 15, 2011): 15980–88. http://dx.doi.org/10.1074/jbc.m110.212597.

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Protein tyrosine phosphorylation is a ubiquitous, fundamental biochemical mechanism that regulates essential eukaryotic cellular functions. The level of tyrosine phosphorylation of specific proteins is finely tuned by the dynamic balance between protein tyrosine kinase and protein tyrosine phosphatase activities. Hepatocyte growth factor receptor (also known as Met), a receptor protein tyrosine kinase, is a major regulator of proliferation, migration, and survival for many epithelial cell types. We report here that receptor-type protein tyrosine phosphatase β (RPTP-β) specifically dephosphorylates Met and thereby regulates its function. Expression of RPTP-β, but not other RPTP family members or catalytically inactive forms of RPTP-β, reduces hepatocyte growth factor (HGF)-stimulated Met tyrosine phosphorylation in HEK293 cells. Expression of RPTP-β in primary human keratinocytes reduces both basal and HGF-induced Met phosphorylation at tyrosine 1356 and inhibits downstream MEK1/2 and Erk activation. Furthermore, shRNA-mediated knockdown of endogenous RPTP-β increases basal and HGF-stimulated Met phosphorylation at tyrosine 1356 in primary human keratinocytes. Purified RPTP-β intracellular domain preferentially dephosphorylates purified Met at tyrosine 1356 in vitro. In addition, the substrate-trapping mutant of RPTP-β specifically interacts with Met in intact cells. Expression of RPTP-β in human primary keratinocytes reduces HGF induction of VEGF expression, proliferation, and motility. Taken together, the above data indicate that RPTP-β is a key regulator of Met function.

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Finlin, Brian S., Angela M. Bodles-Brakhop, Aiwei Yao-Borengasser, Beibei Zhu, Catherine P. Starnes, Robert E. McGehee, Charlotte A. Peterson, Philip A. Kern, and Neda Rasouli. "Regulation of Small Ubiquitin-Like Modifier-1, Nuclear Receptor Coreceptor, Histone Deacetylase 3, and Peroxisome Proliferator-Activated Receptor-γ in Human Adipose Tissue." Metabolic Syndrome and Related Disorders 10, no. 4 (August 2012): 312–17. http://dx.doi.org/10.1089/met.2011.0121.

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Devaraj, Sridevi, Beverley Adams-Huet, and Ishwarlal Jialal. "Endosomal Toll-Like Receptor Status in Patients with Metabolic Syndrome." Metabolic Syndrome and Related Disorders 13, no. 10 (December 2015): 477–80. http://dx.doi.org/10.1089/met.2015.0116.

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Conrotto, Paolo, Donatella Valdembri, Simona Corso, Guido Serini, Luca Tamagnone, Paolo Maria Comoglio, Federico Bussolino, and Silvia Giordano. "Sema4D induces angiogenesis through Met recruitment by Plexin B1." Blood 105, no. 11 (June 1, 2005): 4321–29. http://dx.doi.org/10.1182/blood-2004-07-2885.

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Abstract Semaphorins, a large family of membrane-bound and secreted proteins, signal through their transmembrane receptors, the plexins. Semaphorins and plexins share structural homologies with scatter factor receptors, a family of tyrosine kinase receptors for which Met is the prototype. Semaphorins have been studied primarily in the developing nervous system, where they act as repelling cues in axon guidance. However, they are widely expressed in several tissues, and their role in epithelial morphogenesis has been recently established. Not much is known about their role in angiogenesis, a key step during embryonic development and adulthood. Here we demonstrate that a semaphorin, Sema4D, is angiogenic in vitro and in vivo and that this effect is mediated by its high-affinity receptor, Plexin B1. Moreover, we prove that biologic effects elicited by Plexin B1 require coupling and activation of the Met tyrosine kinase. In sum, we identify a proangiogenic semaphorin and provide insight about the signaling machinery exploited by Plexin B1 to control angiogenesis.

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McIntosh, C. H., X. Jia, and Y. N. Kowk. "Characterization of the opioid receptor type mediating inhibition of rat gastric somatostatin secretion." American Journal of Physiology-Gastrointestinal and Liver Physiology 259, no. 6 (December 1, 1990): G922—G927. http://dx.doi.org/10.1152/ajpgi.1990.259.6.g922.

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The opioid peptides are potent inhibitors of gastric somatostatin-like immunoreactivity (SLI) secretion from the isolated perfused rat stomach. In addition, inhibition of SLI secretion induced by vagal stimulation is partially blocked by naloxone, indicating that endogenously released opioid peptides probably play a physiological role in the regulation of SLI release. The opioid peptides exert their effects by interacting with a number of different receptor types. In the present study, the effect of the selective delta-opioid receptor agonists [D-Pen2.5]enkephalin and [D-Pen2,L-Pen5]enkephalin and the mu-receptor agonist [D-Ala2, N-methyl (NMe)-Phe4,Gly5-ol]enkephalin on gastric inhibitory polypeptide (GIP)-stimulated SLI secretion from the isolated perfused rat stomach have been studied. Responses to the less selective delta-agonist [D-Ala2,D-Leu5]enkephalin, dynorphins 1-8, 1-13, and 1-17, and the extended enkephalin forms Met-enkephalin-Arg6-Phe7,Met- enkephalin-Arg6-Gly7-Leu8, and Met-enkephalin-Arg6-Arg7-Val8-NH2 (metorphamide), have also been investigated. [D-Ala2,NMe-Phe4,Gly5-ol]enkephalin induced a concentration-dependent inhibition of GIP-stimulated SLI secretion, with 50% of maximal inhibition at 10 nM. Neither [D-Pen2.5]enkephalin nor [D-Pen2,L-Pen6]enkephalin (10 nM to 1 microM) had any effect on SLI release, and [D-Ala2,D-Leu5] enkephalin inhibited SLI release only at high concentrations. Met-enkephalin-Arg6-Phe7 and metorphamide both inhibited SLI release, whereas Met-enkephalin-Arg6-Gly7-Leu8 and the dynorphins had little or no effect. In conclusion, the strong inhibition of SLI secretion produced by [D-Ala2,NMe-Phe4,Gly5-ol] enkephalin and lack of major effect of [D-Pen2.5]-enkephalin, [D-Pen2,L-Pen5]enkephalin, and the dynorphins indicate that opioid peptide-induced inhibition was mediated by interaction with mu-receptors and that neither delta or kappa-receptors play a significant role.

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Modica, Chiara, Simona Gallo, Cristina Chiriaco, Martina Spilinga, Paolo Maria Comoglio, Tiziana Crepaldi, Cristina Basilico, and Elisa Vigna. "Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody." Cancers 12, no. 3 (March 21, 2020): 741. http://dx.doi.org/10.3390/cancers12030741.

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The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) inducing the physical removal of the receptor from the cell surface and resulting in suppression of the biological responses to MET. In its bivalent form, the antibody displayed a residual agonist activity, due to dimerization of the lingering receptors, and partial activation of the downstream signaling cascade. The balance between the two opposing activities is variable in different biological systems and is hardly predictable. In this study, we generated and characterized two single-chain antibody fragments derived from DN30, sharing the same variable regions but including linkers different in length and composition. The two engineered molecules bind MET with high affinity but induce different biological responses. One behaves as a MET-antagonist, promoting programmed cell death in MET “addicted” cancer cells. The other acts as a hepatocyte growth factor (HGF)-mimetic, protecting normal cells from doxorubicin-induced apoptosis. Thus, by engineering the same receptor antibody, it is possible to generate molecules enhancing or inhibiting apoptosis either to kill cancer cells or to protect healthy tissues from the injuries of chemotherapy.

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Naline, E., M. Molimard, D. Regoli, X. Emonds-Alt, J. F. Bellamy, and C. Advenier. "Evidence for functional tachykinin NK1 receptors on human isolated small bronchi." American Journal of Physiology-Lung Cellular and Molecular Physiology 271, no. 5 (November 1, 1996): L763—L767. http://dx.doi.org/10.1152/ajplung.1996.271.5.l763.

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On human small isolated bronchi (diameter < 1 mm), but not on larger bronchi (diameter 3-5 mm), substance P (SP) and specific tachykinin SP-preferring neurokinin (NK1) receptor agonists inverted question mark[beta Ala4, Sar9, Met(O2)11]SP-(4-11), [Sar9, Met(O2)11]SP, [Arg6,Sar9,Met(O2)11]SP-(6-11), and septide; 10(-10) to 10(-6) M] produced a concentration-dependent contraction that occurred at low concentrations (pD2 values of 7.79-8.33) and was characterized by a low intrinsic activity [maximal effect (Emax) of 38-45% of Emax induced by 3 mM acetylcholine, in a noncumulative manner]. Comparison of cumulative and noncumulative concentration-response curves to SP and NK1 receptor agonists suggest rapid receptor desensitization. The SP (10(-8) M)-induced contraction was inhibited by tachykinin NK1 receptor antagonists (rank order of potency: SR-140333 > CP-96,345 > RP-67580) but not by the tachykinin NK2 receptor antagonist SR-48968. Indomethacin (10(-6) M) abolished the SP-induced contraction. Our results suggest that tachykinin NK1 receptors are present on human small bronchi and that their stimulation induces a prostanoid-dependent contraction. The small isolated bronchus is an interesting model of human tissue to test NK1 receptor antagonists.

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Grimm, M. C., A. Ben-Baruch, D. D. Taub, O. M. Z. Howard, J. H. Resau, J. M. Wang, H. Ali, R. Richardson, R. Snyderman, and J. J. Oppenheim. "Opiates Transdeactivate Chemokine Receptors: δ and μ Opiate Receptor–mediated Heterologous Desensitization." Journal of Experimental Medicine 188, no. 2 (July 20, 1998): 317–25. http://dx.doi.org/10.1084/jem.188.2.317.

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An intact chemotactic response is vital for leukocyte trafficking and host defense. Opiates are known to exert a number of immunomodulating effects in vitro and in vivo, and we sought to determine whether they were capable of inhibiting chemokine-induced directional migration of human leukocytes, and if so, to ascertain the mechanism involved. The endogenous opioid met-enkephalin induced monocyte chemotaxis in a pertussis toxin–sensitive manner. Met-enkephalin, as well as morphine, inhibited IL-8–induced chemotaxis of human neutrophils and macrophage inflammatory protein (MIP)-1α, regulated upon activation, normal T expressed and secreted (RANTES), and monocyte chemoattractant protein 1, but not MIP-1β–induced chemotaxis of human monocytes. This inhibition of chemotaxis was mediated by δ and μ but not κ G protein–coupled opiate receptors. Calcium flux induced by chemokines was unaffected by met-enkephalin pretreatment. Unlike other opiate-induced changes in leukocyte function, the inhibition of chemotaxis was not mediated by nitric oxide. Opiates induced phosphorylation of the chemokine receptors CXCR1 and CXCR2, but neither induced internalization of chemokine receptors nor perturbed chemokine binding. Thus, inhibition of chemokine-induced chemotaxis by opiates is due to heterologous desensitization through phosphorylation of chemokine receptors. This may contribute to the defects in host defense seen with opiate abuse and has important implications for immunomodulation induced by several endogenous neuropeptides which act through G protein–coupled receptors.

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Journal articles on the topic 'Receptor MET'

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