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Paolo M. Comoglio - One of the best experts on this subject based on the ideXlab platform.
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interplay between Scatter Factor Receptors and b plexins controls invasive growth
Oncogene, 2004Co-Authors: Paolo Conrotto, Simona Corso, Sara Gamberini, Paolo M. Comoglio, Silvia GiordanoAbstract:Met and Ron tyrosine kinases are members of the Scatter Factor Receptor family. Met is the Receptor for hepatocyte growth Factor while Ron is that for macrophage stimulating protein. On ligand stimulation, activation of these Receptors induces ‘invasive growth’, a complex biological response involved in tissue morphogenesis and, when deregulated, in tumor progression and metastasis. Scatter Factor Receptors share structural homology with Plexins, transmembrane Receptors for Semaphorins, a family of ligands originally identified as axon guidance molecules. A physical and functional association between Met and Plexin B1, the prototype of class B Plexin subfamily, has been previously demonstrated. Here, we show that both Met and Ron Receptors can interact with each of the three members of class B Plexins, even in the absence of their ligands and that Plexin B1 ligand, Sema 4D, can induce activation of Met and Ron Receptors, promoting an invasive response. Furthermore, in some human neoplastic cell lines Plexin B1 is overexpressed, constitutively tyrosine phosphorylated, and associated with Scatter Factor Receptors. These data extend the crosstalk previously described between Met and Plexin B1 to the entire families of Scatter Factor Receptors and class B Plexins and show that interaction with multiple upstream activators can finely tune the invasive growth process both in physiological conditions and in tumor growth and metastatization.
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plexin b3 is a functional Receptor for semaphorin 5a
EMBO Reports, 2004Co-Authors: Stefania Artigiani, Paolo Conrotto, Silvia Giordano, Paolo M. Comoglio, Pietro Fazzari, Giorgio F Gilestro, Davide Barberis, Luca TamagnoneAbstract:Semaphorins are a large family of molecular cues implicated in neural development and in a variety of functions outside the nervous system. Semaphorin 5A (Sema5A) is a transmembrane semaphorin, containing seven thrombospondin type-1 repeats, which was recently found to control axon guidance. Here we show that plexin-B3 is a high-affinity Receptor specific for Sema5A. We further demonstrate that plexin-B3 activation by Sema5A mediates functional responses in plexin-B3-expressing cells (either fibroblasts, epithelial and primary endothelial cells). In addition, Sema5A can trigger the intracellular signalling of the hepatocyte growth Factor/Scatter Factor Receptor, Met, associated in a complex with plexin-B3. We thus conclude that Sema5A is able to elicit multiple functional responses through its Receptor plexin-B3.
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a multifunctional docking site mediates signaling and transformation by the hepatocyte growth Factor Scatter Factor Receptor family
Cell, 1994Co-Authors: Carola Ponzetto, Alberto Bardelli, Paolo Dalla Zonca, Z Zhen, George Panayotou, Silvia Giordano, Flavio Maina, Andrea Graziani, Paolo M. ComoglioAbstract:Abstract Signaling by tyrosine kinase Receptors is mediated by selective interactions between individual Src homology 2 (SH2) domains of cytoplasmic effectors and specific phosphotyrosine residues in the activated Receptor. Here, we report the existence in the hepatocyte growth Factor/Scatter Factor (HGFSF) Receptor of a multifunctional docking site made of the tandemly arranged degenerate sequence YVHNV. Phosphorylation of this site mediates intermediate- to high-affinity interactions with multiple SH2-containing signal transducers, including phosphatidylinositol 3-kinase, phospholipase Cγ, pp60 c-src , and the GRB-2-Sos complex. Mutation of the two tyrosines results in loss of biological function, as shown by abrogation of the transforming activity in the oncogenic counterpart of the Receptor. The same bidentate motif is conserved in the evolutionarily related Receptors Sea and Ron, suggesting that in all members of the HGFSF Receptor family, signal transduction is channeled through a multifunctional binding site.
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a protein tyrosine phosphatase activity associated with the hepatocyte growth Factor Scatter Factor Receptor
Journal of Biological Chemistry, 1993Co-Authors: Emma Villamoruzzi, Simone Lapi, Maria Prat, Giovanni Gaudino, Paolo M. ComoglioAbstract:The Receptor for the growth and motility Factor, hepatocyte growth Factor/Scatter Factor (HGF/SF), is a transmembrane tyrosine kinase encoded by the MET oncogene. Previous work has shown that Receptor phosphorylation on tyrosine is critical for both kinase activation and association with intracellular signal transducers. In this paper, we report that a protein tyrosine phosphatase activity (PTP) coprecipitates with the HGF/SF Receptor. The associated PTP activity correlates with the kinase activation of the Receptor, increasing up to 5-fold over the basal level after HGF/SF stimulation. The increase is reversible and time- and dose-dependent. A comparable level of activity is associated with constitutively tyrosine-phosphorylated Receptors immunoprecipitated from cells where the MET oncogene is amplified and overexpressed. In these cells, a parallel decrease in PTP activity is observed after inhibition of Receptor tyrosine phosphorylation following protein kinase C activation. The associated PTP activity is effective in dephosphorylating the HGF/SF Receptor. These data show that a protein tyrosine phosphatase is functionally coupled to the HGF/SF Receptor.
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a novel recognition motif for phosphatidylinositol 3 kinase binding mediates its association with the hepatocyte growth Factor Scatter Factor Receptor
Molecular and Cellular Biology, 1993Co-Authors: Carola Ponzetto, Alberto Bardelli, George Panayotou, Flavio Maina, Paola Longati, R Dhand, Paolo M. ComoglioAbstract:The pleiotropic effects (mitogenesis, motogenesis, and morphogenesis) elicited by hepatocyte growth Factor/Scatter Factor (HGF/SF) are mediated by the activation of the tyrosine kinase Receptor encoded by the MET proto-oncogene. Following autophosphorylation, the Receptor associates with the p85/110 phosphatidylinositol (PI) 3-kinase complex in vivo and in vitro. By a combination of two complementary approaches, competition with synthetic phosphopeptides and association with Tyr-Phe Receptor mutants, we have identified Y-1349 and Y-1356 in the HGF/SF Receptor as the binding sites for PI 3-kinase. Y-1349VHV and Y-1356VNV do not conform to the canonical consensus sequence YXXM for PI 3-kinase binding and thus define YVXV as a novel recognition motif. Y-1349 and Y-1356 are located within the C-terminal portion of the HGF/SF Receptor and are phosphorylation sites. The affinity of the N- and C-terminal src homology region 2 (SH2) domains of p85 for the phosphopeptides including Y-1349 and Y-1356 is 2 orders of magnitude lower than that measured for Y-751 in the platelet-derived growth Factor Receptor binding site. However, the closely spaced duplication of the novel recognition motif in the native HGF/SF Receptor may allow binding with both SH2 domains of p85, thus generating an efficient docking site for PI 3-kinase. In agreement with this model, we have observed that a phosphopeptide including both Y-1349 and Y-1356 activates PI 3-kinase in vitro.
Morag Park - One of the best experts on this subject based on the ideXlab platform.
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hepatocyte growth Factor Receptor tyrosine kinase met is a substrate of the Receptor protein tyrosine phosphatase dep 1
Journal of Biological Chemistry, 2003Co-Authors: Helena L Palka, Morag Park, Nicholas K TonksAbstract:Abstract The Receptor protein-tyrosine phosphatase (PTP) DEP-1 (CD148/PTP-η) has been implicated in the regulation of cell growth, differentiation, and transformation, and most recently has been identified as a potential tumor suppressor gene mutated in colon, lung, and breast cancers. We have generated constructs comprising the cytoplasmic segment of DEP-1 fused to the maltose-binding protein to identify potential substrates and thereby suggest a physiological function for DEP-1. We have shown that the substrate-trapping mutant form of DEP-1 interacted with a small subset of tyrosine-phosphorylated proteins from lysates of the human breast tumor cell lines MDA-MB-231, T-47D, and T-47D/Met and have identified the hepatocyte growth Factor/Scatter Factor Receptor Met, the adapter protein Gab1, and the junctional component p120 catenin as potential substrates. Following ligand stimulation, phosphorylation of specific tyrosyl residues in Met induces mitogenic, motogenic, and morphogenic responses. When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric Receptor colony stimulating Factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr1349) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr1365), whereas tyrosine residues in the activation loop of Met (Tyr1230, Tyr1234, and Tyr1235) were not preferred targets of the PTP. The ability of DEP-1 preferentially to dephosphorylate particular tyrosine residues that are required for Met-induced signaling suggests that DEP-1 may function in controlling the specificity of signals induced by this PTK, rather than as a simple “off-switch” to counteract PTK activity.
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hepatocyte growth Factor Receptor tyrosine kinase met is a substrate of the Receptor protein tyrosine phosphatase dep 1
Journal of Biological Chemistry, 2003Co-Authors: Helena L Palka, Morag Park, Nicholas K TonksAbstract:The Receptor protein-tyrosine phosphatase (PTP) DEP-1 (CD148/PTP-eta) has been implicated in the regulation of cell growth, differentiation, and transformation, and most recently has been identified as a potential tumor suppressor gene mutated in colon, lung, and breast cancers. We have generated constructs comprising the cytoplasmic segment of DEP-1 fused to the maltose-binding protein to identify potential substrates and thereby suggest a physiological function for DEP-1. We have shown that the substrate-trapping mutant form of DEP-1 interacted with a small subset of tyrosine-phosphorylated proteins from lysates of the human breast tumor cell lines MDA-MB-231, T-47D, and T-47D/Met and have identified the hepatocyte growth Factor/Scatter Factor Receptor Met, the adapter protein Gab1, and the junctional component p120 catenin as potential substrates. Following ligand stimulation, phosphorylation of specific tyrosyl residues in Met induces mitogenic, motogenic, and morphogenic responses. When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric Receptor colony stimulating Factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365)), whereas tyrosine residues in the activation loop of Met (Tyr(1230), Tyr(1234), and Tyr(1235)) were not preferred targets of the PTP. The ability of DEP-1 preferentially to dephosphorylate particular tyrosine residues that are required for Met-induced signaling suggests that DEP-1 may function in controlling the specificity of signals induced by this PTK, rather than as a simple "off-switch" to counteract PTK activity.
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efficient cellular transformation by the met oncoprotein requires a functional grb2 binding site and correlates with phosphorylation of the grb2 associated proteins cbl and gab1
Journal of Biological Chemistry, 1997Co-Authors: Elizabeth D Fixman, Marina Holgadomadruga, Linh Nguyen, Darren M Kamikura, Tanya M Fournier, Albert J Wong, Morag ParkAbstract:The Tpr-Met oncoprotein consists of the catalytic kinase domain of the hepatocyte growth Factor/Scatter Factor Receptor tyrosine kinase (Met) fused downstream from sequences encoded by thetpr gene. Tpr-Met is a member of a family of tyrosine kinase oncoproteins generated following genomic rearrangement and has constitutive kinase activity. We have previously demonstrated that a single carboxyl-terminal tyrosine residue, Tyr489, is essential for efficient transformation of Fr3T3 fibroblasts by Tpr-Met and forms a multisubstrate binding site for Grb2, phosphatidylinositol 3′ kinase, phospholipase Cγ, SHP2, and an unknown protein of 110 kDa. A mutant Tpr-Met protein that selectively fails to bind Grb2 has reduced transforming activity, implicating pathways downstream of Grb2 in Tpr-Met mediated cell transformation. We show here that the 110-kDa Tpr-Met substrate corresponds to the recently identified Grb2-associated protein, Gab1. Moreover, we show that tyrosine phosphorylation of the Cbl protooncogene product as well as Gab1 required Tyr489 and correlated with the ability of Tpr-Met to associate with Grb2 and to transform cells, providing evidence that pathways downstream of Gab1 and/or Cbl may play a role in Tpr-Met-mediated cell transformation.
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expression of the met hepatocyte growth Factor Scatter Factor Receptor and its ligand during differentiation of murine p19 embryonal carcinoma cells
Developmental Biology, 1993Co-Authors: Xiuming Yang, Morag ParkAbstract:The met proto-oncogene is a member of the family of tyrosine kinase growth Factor Receptors and was recently identified as a Receptor for hepatocyte growth Factor and Scatter Factor (HGF/SF). From Northern hybridization studies the met/HGF/SF Receptor (R) is expressed in many adult and embryonic mouse tissues. To identify which specific differentiated cell types express the met/HGF/SFR and to investigate the biological function of this Receptor and its ligand during early murine development, we chose to study the expression of the met/HGF/SFR and HGF/SF during differentiation of the pluripotent P19 murine embryonal carcinoma cell line in culture. In this paper we demonstrate that met/HGF/SFR mRNA, protein, and its ligand are expressed at a low level in undifferentiated P19 cells and that their expression is increased as P19 cells are induced to differentiate into neuroectodermal derivatives following treatment with retinoic acid (RA) and into mesodermal derivatives following treatment with dimethyl sulfoxide (DMSO). From in situ hybridization analyses, only a subpopulation of differentiating P19 cells treated with RA or DMSO expresses high levels of the met/HGF/SFR RNA. In cultures treated with RA and cytosine arabinoside, both met/HGF/SFR mRNA and protein can be localized specifically to nondividing neuronal cells. Expression of the met/HGF/SFR and its ligand, HGF/SF, in undifferentiated P19 cells and differentiated derivatives suggests that stimulation of this signal transduction pathway may be an important event for the control of cell differentiation, proliferation, or positioning during embryogenesis.
A Ragab M Shalaby - One of the best experts on this subject based on the ideXlab platform.
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detection of hepatocyte growth Factor Scatter Factor Receptor c met in axillary clearance after mastectomy for breast cancer using reverse transcriptase polymerase chain reaction
DARU, 2007Co-Authors: H El K Refaey, Saed M Naguib, A Ragab M ShalabyAbstract:The diverse biological effects of hepatocyte growth Factor/Scatter Factor (HGF/SF) are mediated by c-Met which is preferentially expressed on epithelial cells. Met signaling has a role in normal cellular activities, and may be associated with development and progression of malignant processes. In this study presence of Met in the axillary drainage from patients who underwent conservative operations for breast cancer, and its prognostic significance was examined. Sixty-two consecutive patients with invasive ductal carcinoma of the breast which were suitable for breast-conserving treatment participated in the study. The output of the drain that had been placed in the axilla during the operation was collected, and the presence of Met and β-actin were assessed by reverse transcriptase-polymerase chain reaction (RTPCR) assays. The data were compared with the pathological features of the tumor and the axillary lymph nodes, and with the estrogen and progesterone Receptors status. RT-PCR of the axillary lymphatic drainage was positive for Met in 46 (74.2%) of the patients and positive assays were correlated with increase in tumor size and grade of capillary and lymphatic invasion, as well as with lymph node metastasis (P < 0.02, for all comparisons). All 24 patients with axillary lymph node metastases in comparison with those without lymph node (57.9%) metastases had positive assays for Met. While all ten patients with tumor involvement in the margins of the resection had positive assays for Met in their lymphatic fluid, only 36 out of 52 patients (69.2%) were positive for met assay. Finally, Met showed negative correlations with positive estrogen and progesterone Receptor assays (P<0.02). From the results of this study it may concluded that Met can be detected in the axillary fluids of patients with breast cancer and its expression in the axillary drainage may be a potential prognostic Factor. This finding might be useful in therapeutic considerations since a positive assay for Met in histologically node-negative patients might indicates the need to search for node microinvasion or involvement of the excision margins with tumor
Ofer Kaplan - One of the best experts on this subject based on the ideXlab platform.
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detection of hepatocyte growth Factor Scatter Factor Receptor c met and muc1 from the axillary fluid drainage in patients after breast cancer surgery
Israel Medical Association Journal, 2003Co-Authors: Ron Greenberg, Yoav Barnea, Shiomo Schneebaum, Hanoch Kashtan, Ofer Kaplan, Yehuda SkornikAbstract:Background: Drains are inserted in the dissected axilla of most patients during surgery for breast cancer. Objective: To evaluate the presence and prognostic value of MUC1 and Met-hepatocyte growth Factor/Scatter Factor in the axillary drainage of these patients. Methods: The study group included 40 consecutive patients with invasive ductat carcinoma of the breast who were suitable for breast-conserving treatment; 20 malignant melanoma patients found to have negative axillary sentinel lymph node served as the control group, The output of the drains, which had been placed in the axilla during operation, was collected, and the presence of MUC1, Met-HGF/SF and β-actin were assessed in the lymphatic fluid by reverse transcription-polymerase chain reaction assays. The data were compared to the pathologic features of the tumor and the axillary lymph nodes, and to the estrogen and progesterone Receptors status. Results: RT-PCR assays of the axillary lymphatic drainage were positive for MUC1 and Met-HGF/SF in 15 (37.5%) and 26 (65%) of the patients, respectively. Patients in whom MUC1 and Met-HGF/ SF were not found in the axillary fluid had smaller tumors and less capillary and lymphatic invasions compared to patients with positive assays (P < 0.0 or all these comparisons). The lymph nodes were negative for metastases in all patients with negative assays (P < 0.001). The presence of MUC1 and Met-HGF/SF showed negative correlations with the estrogen and progesterone Receptors (P < 0.05). Conclusion: MUC1 and Met-HGF/SF can be detected in the axillary fluids of patients with breast cancer. The expression of both tumor markers in the axillary drainage is strongly associated with unfavorable tumor features and can be used as a prognostic Factor.
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detection of hepatocyte growth Factor Scatter Factor Receptor c met in axillary drainage after operations for breast cancer using reverse transcriptase polymerase chain reaction
Breast Cancer Research, 2003Co-Authors: Ron Greenberg, Ignat Schwartz, Yehuda Skornick, Ofer KaplanAbstract:The diverse biological effects of hepatocyte growth Factor/Scatter Factor (HGF/SF) are mediated by c-Met, which is preferentially expressed on epithelial cells. Met signaling has a role in normal cellular activities, and may be associated with the development and progression of malignant processes. In this study we examined whether Met can be detected in the axillary drainage from patients who underwent conservative operations for breast cancer, and its prognostic significance. Thirty-one consecutive patients with invasive ductal carcinoma of the breast suitable for breast-conserving treatment were studied. The output of the drain that had been placed in the axilla during the operation was collected, and the presence of Met and β-actin were assessed by reverse transcriptase–polymerase chain reaction (RT–PCR) assays. The data were compared with the pathological features of the tumor and the axillary lymph nodes, and with the estrogen Receptor and progesterone Receptor status. RT–PCR of the axillary lymphatic drainage was positive for Met in 23 (74.2%) of the patients. Positive assays were correlated with increasing tumor size and grade, with capillary and lymphatic invasion, and with lymph node metastasis (P < 0.02, for all comparisons). All 12 patients with axillary lymph node metastases had positive assays for Met, compared with 57.9% of patients without lymph node metastases. All five patients with tumor involvement in the margins of the resection had positive assays for Met in their lymphatic fluid, compared with 18 of 26 positive assays (69.2%) for patients without involved margins (P < 0.04). Finally, Met showed negative correlations with positivity for estrogen Receptor and progesterone Receptor (P < 0.02). Met can be detected in the axillary fluids of patients with breast cancer and its expression in the axillary drainage may have potential as a prognostic Factor. This finding might be relevant to therapeutic considerations, because a positive assay for Met in histologically node-negative patients might point to the need to search for node microinvasion or involvement of the excision margins with tumor.
Nicholas K Tonks - One of the best experts on this subject based on the ideXlab platform.
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hepatocyte growth Factor Receptor tyrosine kinase met is a substrate of the Receptor protein tyrosine phosphatase dep 1
Journal of Biological Chemistry, 2003Co-Authors: Helena L Palka, Morag Park, Nicholas K TonksAbstract:Abstract The Receptor protein-tyrosine phosphatase (PTP) DEP-1 (CD148/PTP-η) has been implicated in the regulation of cell growth, differentiation, and transformation, and most recently has been identified as a potential tumor suppressor gene mutated in colon, lung, and breast cancers. We have generated constructs comprising the cytoplasmic segment of DEP-1 fused to the maltose-binding protein to identify potential substrates and thereby suggest a physiological function for DEP-1. We have shown that the substrate-trapping mutant form of DEP-1 interacted with a small subset of tyrosine-phosphorylated proteins from lysates of the human breast tumor cell lines MDA-MB-231, T-47D, and T-47D/Met and have identified the hepatocyte growth Factor/Scatter Factor Receptor Met, the adapter protein Gab1, and the junctional component p120 catenin as potential substrates. Following ligand stimulation, phosphorylation of specific tyrosyl residues in Met induces mitogenic, motogenic, and morphogenic responses. When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric Receptor colony stimulating Factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr1349) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr1365), whereas tyrosine residues in the activation loop of Met (Tyr1230, Tyr1234, and Tyr1235) were not preferred targets of the PTP. The ability of DEP-1 preferentially to dephosphorylate particular tyrosine residues that are required for Met-induced signaling suggests that DEP-1 may function in controlling the specificity of signals induced by this PTK, rather than as a simple “off-switch” to counteract PTK activity.
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hepatocyte growth Factor Receptor tyrosine kinase met is a substrate of the Receptor protein tyrosine phosphatase dep 1
Journal of Biological Chemistry, 2003Co-Authors: Helena L Palka, Morag Park, Nicholas K TonksAbstract:The Receptor protein-tyrosine phosphatase (PTP) DEP-1 (CD148/PTP-eta) has been implicated in the regulation of cell growth, differentiation, and transformation, and most recently has been identified as a potential tumor suppressor gene mutated in colon, lung, and breast cancers. We have generated constructs comprising the cytoplasmic segment of DEP-1 fused to the maltose-binding protein to identify potential substrates and thereby suggest a physiological function for DEP-1. We have shown that the substrate-trapping mutant form of DEP-1 interacted with a small subset of tyrosine-phosphorylated proteins from lysates of the human breast tumor cell lines MDA-MB-231, T-47D, and T-47D/Met and have identified the hepatocyte growth Factor/Scatter Factor Receptor Met, the adapter protein Gab1, and the junctional component p120 catenin as potential substrates. Following ligand stimulation, phosphorylation of specific tyrosyl residues in Met induces mitogenic, motogenic, and morphogenic responses. When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric Receptor colony stimulating Factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365)), whereas tyrosine residues in the activation loop of Met (Tyr(1230), Tyr(1234), and Tyr(1235)) were not preferred targets of the PTP. The ability of DEP-1 preferentially to dephosphorylate particular tyrosine residues that are required for Met-induced signaling suggests that DEP-1 may function in controlling the specificity of signals induced by this PTK, rather than as a simple "off-switch" to counteract PTK activity.
