The many faces of Src: multiple functions of a prototypical tyrosine kinase

Schwartzberg, Pamela L.

doi:10.1038/sj.onc.1202176

Cited by 140 publications

(164 citation statements)

References 39 publications

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“…The Src family of non-receptor tyrosine kinases mediates a variety of signaling pathways (15). Src family kinases have unique N-terminal and SH2 and SH3 domains that mediate protein/protein interactions and a C-terminal SH1 tyrosine kinase domain (15,16).…”

mentioning

confidence: 99%

“…Src family kinases have unique N-terminal and SH2 and SH3 domains that mediate protein/protein interactions and a C-terminal SH1 tyrosine kinase domain (15,16). Protein-tyrosine kinases of the Src family are involved in the transduction of signals from multiple transmembrane tyrosine kinase receptors, including epidermal growth factor (EGF) (16), platelet-derived growth factor (PDGF) (17), and FGF (18 -21).…”

mentioning

confidence: 99%

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Cbl-mediated Degradation of Lyn and Fyn Induced by Constitutive Fibroblast Growth Factor Receptor-2 Activation Supports Osteoblast Differentiation

Kaabeche

Lemonnier²,

Mée

et al. 2004

Journal of Biological Chemistry

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confidence: 99%

Cbl-mediated Degradation of Lyn and Fyn Induced by Constitutive Fibroblast Growth Factor Receptor-2 Activation Supports Osteoblast Differentiation

Kaabeche

Lemonnier²,

Mée

et al. 2004

Journal of Biological Chemistry

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“…Thus at this point in time we cannot rule out a role for this molecule in the v-Src-induced upregulation of Bcl-x L expression in IEC-18 cells. In fact, it is now well established that the full oncogenic activities of v-Src are mediated by multiple pathways (Odajima et al, 2000;Penuel and Martin, 1999;Schwartzberg, 1998) and it is certainly conceivable that both MEK and Stat3 contribute to the induction of Bcl-x L expression in intestinal epithelial cells.…”

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Increased Bcl-xL expression mediates v-Src-induced resistance to anoikis in intestinal epithelial cells

et al. 2002

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Acquisition of resistance to anoikis (detachment-induced apoptosis) is considered to be a requirement for transformed intestinal epithelial cells to invade surrounding tissues and metastasize to distant organs. Increased Src kinase activity, which is a feature of a large proportion of colorectal cancers, has been identi®ed as one of the factors that can contribute to anoikis resistance. However, the molecular mechanism by which high levels of Src activity contribute to anoikis resistance in intestinal epithelial cells is unknown. Here we show that high Src activity confers resistance to anoikis in intestinal epithelial cells, at least in part, by inducing Bcl-x L overexpression, and that this induction is mediated by the MEK/MAPK pathway. Based on the ®ndings reported here, and on our previous study showing that Bcl-x L plays a critical role in ras-induced resistance to anoikis, we propose that the increased Bclx L levels found in colorectal cancers play a signi®cant role in the induction of resistance to anoikis during the progression of this disease.

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“…Src family kinases have a conserved topology, consisting of a myristoylated amino terminus, a variable region, Src homology 3 (SH3) 1 and SH2 domains, a linker region, a catalytic domain, and a regulatory tail (1)(2)(3). In unstimulated cells, catalytic activity is repressed by two intramolecular interactions, one involving the SH3 domain and a proline-containing motif in the linker region, and another involving the SH2 domain and a phosphorylated tyrosine in the tail region (Tyr-527 in chicken Src) (1,3). Dephosphorylation or mutation of this tyrosine, or engagement of the SH3 or SH2 domains with specific ligands, results in enzymatic activation.…”

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confidence: 99%

Independent SH2-binding Sites Mediate Interaction of Dok-related Protein with RasGTPase-activating Protein and Nck

Lock

Casagranda

Dunn

1999

Journal of Biological Chemistry

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A murine embryonic cDNA library was screened for potential substrates of the Src family kinase, Lyn, using a phosphorylation-screening strategy. One cDNA that we identified encodes Dok-related protein (DokR), a protein with homology to p62 dok (Dok), and members of the insulin receptor substrate-1 family of proteins. Analysis of murine tissue extracts with DokR-specific antisera revealed that DokR protein is expressed at highest levels in lymphoid tissues. Co-expression of a FLAG epitope-tagged form of DokR (FLAG-DokR) with Lyn in embryonic kidney 293T cells resulted in constitutive phosphorylation of FLAG-DokR on tyrosine residues and consequential physical association with RasGTPase-activating protein (GAP) and the Nck adaptor protein. Stimulation of BaF/3 hematopoietic cells co-expressing the epidermal growth factor (EGF) receptor tyrosine kinase and FLAG-DokR with EGF also induced phosphorylation of FLAG-DokR and promoted its association with GAP. Immunoprecipitation experiments using DokR-specific antibodies revealed an interaction between endogenous DokR and a 150-kDa protein that is tyrosine-phosphorylated in EGF-stimulated BaF/3 cells. The molecular basis of the interactions involving DokR with GAP and Nck was investigated using a novel glutathione S-transferase fusion protein binding assay and/or site-directed mutagenesis. Tandem SH2-binding sites containing Tyr-276 and Tyr-304 were shown to mediate binding of DokR to GAP, whereas Tyr-351 mediated the binding of DokR to Nck. These results suggest that DokR participates in numerous signaling pathways.On the basis of their capacity for oncogenic transformation, Src family kinases have long been suspected to regulate cell growth and differentiation (1). In mammals, eight Src family kinases have been identified as follows: Src, Yes, Fgr, Fyn, Lyn, Hck, Lck, and Blk. Src family kinases have a conserved topology, consisting of a myristoylated amino terminus, a variable region, Src homology 3 (SH3) 1 and SH2 domains, a linker region, a catalytic domain, and a regulatory tail (1-3). In unstimulated cells, catalytic activity is repressed by two intramolecular interactions, one involving the SH3 domain and a proline-containing motif in the linker region, and another involving the SH2 domain and a phosphorylated tyrosine in the tail region (Tyr-527 in chicken Src) (1, 3). Dephosphorylation or mutation of this tyrosine, or engagement of the SH3 or SH2 domains with specific ligands, results in enzymatic activation. Src family kinases are associated with cell membranes via a myristoylated amino terminus and are physically or functionally coupled in different cell types to diverse cell surface molecules, including integrins, G-protein-coupled receptors, growth factor receptors, and antigen and antibody receptors (1). Numerous candidate substrates have been identified that are phosphorylated on tyrosine residues by Src family tyrosine kinases, including non-receptor tyrosine kinases (4 -6), structural proteins implicated in cytoskeletal regulation (7-9), docking protei...

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The many faces of Src: multiple functions of a prototypical tyrosine kinase

Cited by 140 publications

References 39 publications

Cbl-mediated Degradation of Lyn and Fyn Induced by Constitutive Fibroblast Growth Factor Receptor-2 Activation Supports Osteoblast Differentiation

Cbl-mediated Degradation of Lyn and Fyn Induced by Constitutive Fibroblast Growth Factor Receptor-2 Activation Supports Osteoblast Differentiation

Increased Bcl-xL expression mediates v-Src-induced resistance to anoikis in intestinal epithelial cells

Independent SH2-binding Sites Mediate Interaction of Dok-related Protein with RasGTPase-activating Protein and Nck

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