Tyrosine 1356 in the carboxyl-terminal tail of the HGF/SF receptor is essential for the transduction of signals for cell motility and morphogenesis.

Zhu, Hong; Naujokas, Monica A.; Fixman, Elizabeth D.; Torossian, Krikor; Park, M.

doi:10.1016/s0021-9258(18)43972-5

Cited by 117 publications

(13 citation statements)

References 29 publications

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“…Mice that carry mutations in the Grb2-binding site (Y1356VNV to 1356VHV) of c-Met develop to term but also show muscle defects. Similarly, it was shown by in vitro experiments that Y14 and Y15 of c-Met are required for c-Met-specific branching morphogenesis of MDCK cells (Zhu et al, 1994;Weidner et al, 1995;Sachs et al, 1996).…”

Section: Introductionmentioning

confidence: 65%

Coupling of Gab1 to C-Met, Grb2, and Shp2 Mediates Biological Responses

Schaeper

Gehring

Fuchs

et al. 2000

The Journal of Cell Biology

314

322

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Gab1 is a substrate of the receptor tyrosine kinase c-Met and involved in c-Met–specific branching morphogenesis. It associates directly with c-Met via the c-Met–binding domain, which is not related to known phosphotyrosine-binding domains. In addition, Gab1 is engaged in a constitutive complex with the adaptor protein Grb2. We have now mapped the c-Met and Grb2 interaction sites using reverse yeast two-hybrid technology. The c-Met–binding site is localized to a 13–amino acid region unique to Gab1. Insertion of this site into the Gab1-related protein p97/Gab2 was sufficient to confer c-Met–binding activity. Association with Grb2 was mapped to two sites: a classical SH3-binding site (PXXP) and a novel Grb2 SH3 consensus-binding motif (PX(V/I)(D/N)RXXKP). To detect phosphorylation-dependent interactions of Gab1 with downstream substrates, we developed a modified yeast two-hybrid assay and identified PI(3)K, Shc, Shp2, and CRKL as interaction partners of Gab1. In a trk-met-Gab1–specific branching morphogenesis assay, association of Gab1 with Shp2, but not PI(3)K, CRKL, or Shc was essential to induce a biological response in MDCK cells. Overexpression of a Gab1 mutant deficient in Shp2 interaction could also block HGF/SF-induced activation of the MAPK pathway, suggesting that Shp2 is critical for c-Met/Gab1-specific signaling.

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Section: Introductionmentioning

confidence: 65%

Coupling of Gab1 to C-Met, Grb2, and Shp2 Mediates Biological Responses

Schaeper

Gehring

Fuchs

et al. 2000

The Journal of Cell Biology

314

322

View full text Add to dashboard Cite

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“…Apparently, c-Met can transmit some signals in the absence of Gab1. The multiple docking site of c-Met binds not only Gab1, but can also directly associate with signaling molecules like p85 PI(3) kinase, Shc, phospholipase C␥, and Shp2, which are also recruited by Gab1 (Ponzetto et al, 1994;Zhu et al, 1994;Fixman et al, 1995;Pelicci et al, 1995;Schaeper et al, 2000). Moreover, it is possible that additional docking proteins contribute to the transmission of the c-Met signal that controls migration of muscle precursor cells.…”

Section: Discussionmentioning

confidence: 99%

“…Two phosphorylated tyrosyl residues in c-Met, Y1349 and Y1356, are essential for its function in vitro and in vivo (Ponzetto et al, 1994;Fixman et al, 1995;Weidner et al, 1995;Maina et al, 1996;Sachs et al, 1996;Giordano et al, 1997). These residues constitute a bivalent docking site that recruits various signaling and adapter proteins like PI(3) kinase, phospholipase C ␥ , Src, Shc, Grb2, and Gab1 (Ponzetto et al, 1994;Zhu et al, 1994;Fixman et al, 1995;Pelicci et al, 1995;Weidner et al, 1996). Gab1 requires Y1349 and, to a lesser degree Y1356, for binding to the c-Met receptor (Holgado-Madruga et al, 1996;.…”

Section: Introductionmentioning

confidence: 99%

Essential Role of Gab1 for Signaling by the C-Met Receptor in Vivo

Sachs

Brohmann

Zechner

et al. 2000

The Journal of Cell Biology

242

196

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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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“…cytoplasmic transducers containing SH2 domains, 61,62 including the p85 subunit of phosphatidylinositol 3-kinase (PI3kinase), phospholipase Cg, RasGAP, Grb2-Sos complex, ACKNOWLEDGMENT and Src-related tyrosine kinases. [63][64][65][66] For scattering of epithe-We thank Dr E. Roos (Department of Cell Biology, Netherlands lial cells, besides these second messengers, an additional Cancer Institute, Amsterdam) and Drs A. Hekman (Department of signal is required, which could be provided by positive sig-Immunology, Netherlands Cancer Institute) for the very helpful disnals resulting from FN receptors as has been indicated by cussions and the critical reading of this manuscript. Furthermore, experiments with MDCK cells.…”

Section: C-met Expression In B-lymphoma Cellsmentioning

confidence: 99%

Hepatocyte Growth Factor/Scatter Factor Promotes Adhesion of Lymphoma Cells to Extracellular Matrix Molecules Via α4β1 and α5β1 Integrins

Weimar

Jong

Muller

et al. 1997

Blood

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Hepatocyte growth factor (HGF )/scatter factor (SF ) is the ligand for a tyrosine kinase cell surface receptor encoded by the MET protooncogene (c-MET). HGF/SF can induce proliferation and motility in epithelial cells and promotes invasion of carcinoma cells and NIH3T3 fibroblasts transfected with both HGF/SF and c-MET genes. Our results show that HGF/SF and c-MET also play a role in adhesion and invasion of human lymphoma cells. c-MET mRNA is expressed in hemopoietic cells, such as hemopoietic progenitor cells (CD34+ cells) in bone marrow (BM) and mobilized peripheral blood, immature B cells in cord blood and BM, and germinal center B-centroblasts. In normal peripheral blood B cells, which are c-MET−, c-MET expression was induced by PMA, ConA, HGF/SF, and Epstein-Barr virus (EBV) infection. Using immunohistochemistry, we detected c-MET on the cell surface of large activated centroblasts in lymph nodes from patients with B-non–Hodgkin's lymphoma and Hodgkin's disease. In the latter group, c-MET expression correlated well with the presence of EBV. Because HGF/SF and c-MET promote metastasis of carcinoma cells, we studied the effects of c-MET stimulation by HGF/SF of B-lymphoma cells on properties relevant for metastasis, ie, adhesion, migration, and invasion. HGF/SF stimulated adhesion of the c-MET+ B-cell lines to the extracellular matrix molecules fibronectin (FN) and collagen (CN) in a dose dependent manner. However, adhesion to laminin was not affected by HGF/SF. Adhesion to FN was mediated by β1-integrins α4β1 (VLA4) and α5β1 (VLA5) since blocking antibodies against β1- (CD29), α4- (CD49d), or α5- (CD49e) integrin subunits, completely reversed the effect of HGF/SF. Furthermore, HGF/SF induced adhesion was abrogated by addition of genistein, which blocks protein tyrosine kinases, including c-MET. Addition of HGF/SF resulted in a sixfold increase in migration of c-MET B-lymphoma cells through Matrigel, compared to medium alone. In rat fibroblast cultures, HGF/SF doubled the number of c-MET+ B-lymphoma cells that invaded the fibroblast monolayer. In these adhesion, migration and invasion assays HGF/SF had no effect on c-MET− cell lines. In conclusion, c-MET is expressed or can be induced on immature, activated, and certain malignant B cells. HGF/SF increased adhesion of c-MET+ B-lymphoma cells to FN and CN, mediated via β1-integrins α4β1 and α5β1 , and furthermore promoted migration and invasion.

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Tyrosine 1356 in the carboxyl-terminal tail of the HGF/SF receptor is essential for the transduction of signals for cell motility and morphogenesis.

Cited by 117 publications

References 29 publications

Coupling of Gab1 to C-Met, Grb2, and Shp2 Mediates Biological Responses

Coupling of Gab1 to C-Met, Grb2, and Shp2 Mediates Biological Responses

Essential Role of Gab1 for Signaling by the C-Met Receptor in Vivo

Hepatocyte Growth Factor/Scatter Factor Promotes Adhesion of Lymphoma Cells to Extracellular Matrix Molecules Via α4β1 and α5β1 Integrins

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