Adaptor Protein Shc Is an Isoform-specific Direct Activator of the Tyrosine Kinase c-Src

Sato, Kenichi; Nagao, Tomomi; Kakumoto, Miki; Kimoto, Miwa; Otsuki, Tetsuji; Iwasaki, Tetsushi; Tokmakov, Alexander A.; Owada, Koji; Fukami, Yasuo

doi:10.1074/jbc.m203179200

Cited by 61 publications

(61 citation statements)

References 49 publications

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“…Tyrosine residues 239 and 240 of Shc can be phosphorylated by Src (43), and Src only interacts with the two larger isoforms of Shc, but not with p46 (43,47). We only observed an effect on the small isoform.…”

Section: Discussionmentioning

confidence: 47%

Sequence-specific Peptide Aptamers, Interacting with the Intracellular Domain of the Epidermal Growth Factor Receptor, Interfere with Stat3 Activation and Inhibit the Growth of Tumor Cells

Buerger

Nagel-Wolfrum

Künz

et al. 2003

Journal of Biological Chemistry

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Receptor tyrosine kinases of the epidermal growth factor (EGF) receptor family regulate essential cellular functions such as proliferation, survival, migration, and differentiation but also play central roles in the etiology and progression of tumors. We have identified short peptide sequences from a random peptide library integrated into the thioredoxin scaffold protein, which specifically bind to the intracellular domain of the EGF receptor (EGFR). These molecules have the potential to selectively inhibit specific aspects of EGF receptor signaling and might become valuable as anticancer agents. Intracellular expression of the aptamer encoding gene construct KDI1 or introduction of bacterially expressed KDI1 via a protein transduction domain into EGFR-expressing cells results in KDI1⅐EGF receptor complex formation, a slower proliferation, and reduced soft agar colony formation. Aptamer KDI1 did not summarily block the EGF receptor tyrosine kinase activity but selectively interfered with the EGF-induced phosphorylation of the tyrosine residues 845, 1068, and 1148 as well as the phosphorylation of tyrosine 317 of p46 Shc. EGFinduced phosphorylation of Stat3 at tyrosine 705 and Stat3-dependent transactivation were also impaired. Transduction of a short synthetic peptide aptamer sequence not embedded into the scaffold protein resulted in the same impairment of EGF-induced Stat3 activation.

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Section: Discussionmentioning

confidence: 47%

Sequence-specific Peptide Aptamers, Interacting with the Intracellular Domain of the Epidermal Growth Factor Receptor, Interfere with Stat3 Activation and Inhibit the Growth of Tumor Cells

Buerger

Nagel-Wolfrum

Künz

et al. 2003

Journal of Biological Chemistry

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“…Weng et al (43) reported that their interaction was mediated through the SH3 domain of Src and proline-rich region of Shc. A second type of interaction was described by Sato et al (39,44) who demonstrated that Src and Shc interact through the activation segment of Src and a specific 19-amino acid sequence in the N-terminal region of Shc. We addressed both possibilities using cells that expressed two different Shc mutants, e.g.…”

Section: Discussionmentioning

confidence: 99%

The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells

Lieskovská

Ling

Badley-Clarke

et al. 2006

Journal of Biological Chemistry

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Activation of the MAPK pathway mediates insulin-like growth factor-I (IGF-I)-dependent proliferation in vascular smooth muscle cells (SMC).Our previous studies have shown that IGF-I-induced Shc phosphorylation is necessary for sustained activation of MAPK and increased cell proliferation of SMCs, and both Shc and the tyrosine phosphatase SHP-2 must be recruited to the membrane protein SHPS-1 in order for Shc to be phosphorylated. These studies were undertaken to determine whether Src kinase activity is required to phosphorylate Shc in response to IGF-I in SMC and because SHP-2 binds to Src whether their interaction was also required for IGF-I-stimulated mitogenesis. Our results show that IGF-I induces activation of Src kinase and that is required for Shc phosphorylation and for optimal MAPK activation. We tested whether Shc is a substrate of c-Src in SMC by disrupting Src/Shc association using a peptide containing a YXXL (Tyr 328 ) motif sequence derived from Src. The peptide blocked the binding of Src and Shc in vitro and in vivo. Cells expressing a mutant Src (Src-FF) that had Tyr 328 / Tyr 358 substituted with phenylalanines (Src-FF) showed defective Src/Shc binding, impaired IGF-I-dependent Shc phosphorylation, and impaired mitogenesis. This supports the conclusion that Src phosphorylates Shc. IGF-I induced both Src/SHP-2 and Src/SHPS-1 association. SMCs expressing an SHP-2 mutant that had the polyproline-rich region of SH2 deleted (SHP-2⌬10) had disrupted SHP-2/Src association, impaired IGF-I-dependent Shc phosphorylation, and an attenuated mitogenic response. IGF-I-induced association of Src and SHPS-1 was also impaired in SHP-2⌬10-expressing cells, although SHP-2/SHPS-1 association was unaffected. Upon IGF-I stimulation, a complex assembles on SHPS-1 that contains SHP-2, c-Src, and Shc wherein Src phosphorylates Shc, a signaling step that is necessary for an optimal mitogenic response. IGF-I2 stimulation of vascular smooth muscle cells (SMC) leads to activation of two major signaling pathways, e.g. the MAP kinase (MAPK) and PI 3-kinase pathways (1). Activation of the MAPK pathway is required for IGF-I-dependent proliferation, whereas activation of the PI 3-kinase pathway is the predominant determinant of IGF-I-dependent SMC migration. BindingofIGF-ItotheIGF-Ireceptorleadstoreceptorautophosphorylation followed by tyrosine phosphorylation of substrates such as IRS-1 and Shc (2). These adaptor proteins bind Grb2/ SOS and activate the Ras/MAPK pathway (3). Previous studies in SMC have shown that IGF-I-induced Shc phosphorylation and its association with Grb-2 are necessary for sustained phosphorylation of Erk1/2 MAPK and IGF-I-dependent cell proliferation (4). The requirement of Shc phosphorylation for growth factor-dependent mitogenesis has been demonstrated in other cell types as well (5, 6).Src family kinases (SFK) have been implicated in mediating the mitogenic effect of several growth factors (7, 8); however, the mechanism by which SFK function is not completely understood. Src has also been implicated i...

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“…The different roles of ShcA isoforms in the intracellular networks are largely unknown. Indeed, evidence of a functional divergences between them had been reported previously (50,51). For example, the presence of the amino-terminal extension in p52Shc affects the affinity of the PTB for phosphotyrosine-containing proteins, which is approximately 10 times lower for p46Shc (50), and the region comprised between residues 29 and 45 of p52Shc, which is absent in p46Shc, is responsible for the interaction of p52 (and p66Shc) with c-Src (51).…”

Section: Discussionmentioning

confidence: 99%

Adaptor ShcA Protein Binds Tyrosine Kinase Tie2 Receptor and Regulates Migration and Sprouting but Not Survival of Endothelial Cells

Audero

Cascone

Maniero

et al. 2004

Journal of Biological Chemistry

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Adaptor Protein Shc Is an Isoform-specific Direct Activator of the Tyrosine Kinase c-Src

Cited by 61 publications

References 49 publications

Sequence-specific Peptide Aptamers, Interacting with the Intracellular Domain of the Epidermal Growth Factor Receptor, Interfere with Stat3 Activation and Inhibit the Growth of Tumor Cells

Sequence-specific Peptide Aptamers, Interacting with the Intracellular Domain of the Epidermal Growth Factor Receptor, Interfere with Stat3 Activation and Inhibit the Growth of Tumor Cells

The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells

Adaptor ShcA Protein Binds Tyrosine Kinase Tie2 Receptor and Regulates Migration and Sprouting but Not Survival of Endothelial Cells

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