Tyrosine Residues 239 and 240 of Shc Are Phosphatidylinositol 4,5-Bisphosphate-Dependent Phosphorylation Sites by c-Src

Sato, Kenichi; Gotoh, Noriko; Otsuki, Tetsuji; Kakumoto, Miki; Aoto, Mamoru; Tokmakov, Alexander A.; Shibuya, Masabumi; Fukami, Yasuo

doi:10.1006/bbrc.1997.7667

Cited by 29 publications

(17 citation statements)

References 23 publications

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“…Others have shown a role for Shc Tyr239-Tyr240 and Shc Tyr317 phosphorylation in Grb2 binding and Ras-MAP kinase pathway activation (26,32). In addition, phosphorylation of Tyr239-Tyr240 in response to cytokines has been implicated in a Ras-independent pathway leading to c-Myc (8), and phosphorylation of these two residues by Src appears to be stimulated in some way by PIP2 binding to Shc (27,28). To explore the potential role of Shc molecules phosphorylated at each of these sites, we tested the effects of wild-type and mutant Shc proteins on PDGF-stimulated DNA synthesis, using plasmid DNA microinjection.…”

Section: Resultsmentioning

confidence: 99%

“…A Shc ⌬PTB domain deletion mutant also blocked PDGF-stimulated DNA synthesis. Others have shown that the Shc PTB domain binding to PIP2 may stimulate Src phosphorylation of Tyr239-Tyr240 through an as-yet-unknown mechanism-perhaps by causing colocalization of Src and Shc following growth factor receptor activation of phosphatidylinositol 3 kinase (27,28). Both inhibitory Shc mutants (2Y2F-R401K and ⌬PTB) could be rescued by Myc coexpression but not by Fos, suggesting that these Shc domains are required in the Src pathway.…”

Section: Discussionmentioning

confidence: 99%

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SU6656, a Selective Src Family Kinase Inhibitor, Used To Probe Growth Factor Signaling

Blake¹,

Broome²,

Liu³

et al. 2000

Molecular and Cellular Biology

548

463

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The use of small-molecule inhibitors to study molecular components of cellular signal transduction pathways provides a means of analysis complementary to currently used techniques, such as antisense, dominantnegative (interfering) mutants and constitutively activated mutants. We have identified and characterized a small-molecule inhibitor, SU6656, which exhibits selectivity for Src and other members of the Src family. A related inhibitor, SU6657, inhibits many kinases, including Src and the platelet-derived growth factor (PDGF) receptor. The use of SU6656 confirmed our previous findings that Src family kinases are required for both Myc induction and DNA synthesis in response to PDGF stimulation of NIH 3T3 fibroblasts. By comparing PDGFstimulated tyrosine phosphorylation events in untreated and SU6656-treated cells, we found that some substrates (for example, c-Cbl, and protein kinase C ␦) were Src family substrates whereas others (for example, phospholipase C-␥) were not. One protein, the adaptor Shc, was a substrate for both Src family kinases (on tyrosines 239 and 240) and a distinct tyrosine kinase (on tyrosine 317, which is perhaps phosphorylated by the PDGF receptor itself). Microinjection experiments demonstrated that a Shc molecule carrying mutations of tyrosines 239 and 240, in conjunction with an SH2 domain mutation, interfered with PDGF-stimulated DNA synthesis. Deletion of the phosphotyrosine-binding domain also inhibited synthesis. These inhibitions were overcome by heterologous expression of Myc, supporting the hypothesis that Shc functions in the Src pathway. SU6656 should prove a useful additional tool for further dissecting the role of Src kinases in this and other signal transduction pathways.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SU6656, a Selective Src Family Kinase Inhibitor, Used To Probe Growth Factor Signaling

Blake¹,

Broome²,

Liu³

et al. 2000

Molecular and Cellular Biology

548

463

View full text Add to dashboard Cite

show abstract

“…Some studies suggest that the ShcA/Src complex is constitutive (42) whereas others show that Src binds inducibly to the SH2 domain of ShcA (33). Moreover, ShcA recruitment increases Src activity (42) and the Y239/Y240 residues within the CH1 domain of ShcA are Src phosphorylation sites (43). Thus, ShcA and Src complexes potentiate signal transduction in a reciprocal manner.…”

Section: Discussionmentioning

confidence: 99%

The ShcA PTB Domain Functions as a Biological Sensor of Phosphotyrosine Signaling during Breast Cancer Progression

Ahn

Sabourin

et al. 2013

Cancer Research

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ShcA (SHC1) is an adapter protein that possesses an SH2 and a PTB phosphotyrosine-binding motif. ShcA generally uses its PTB domain to engage activated receptor tyrosine kinases (RTK), but there has not been a definitive determination of the role of this domain in tumorigenesis. To address this question, we employed a ShcA mutant (R175Q) that no longer binds phosphotyrosine residues via its PTB domain. Here, we report that transgenic expression of this mutant delays onset of mammary tumors in the MMTV-PyMT mouse model of breast cancer. Paradoxically, we observed a robust increase in the growth and angiogenesis of mammary tumors expressing ShcR175Q, which displayed increased secretion of fibronectin and expression of integrin a5/b1, the principal fibronectin receptor. Sustained integrin engagement activated Src, which in turn phosphorylated proangiogenic RTKs, including platelet-derived growth factor receptor, fibroblast growth factor receptor, and Met, leading to increased VEGF secretion from ShcR175Q-expressing breast cancer cells. We defined a ShcR175Q-dependent gene signature that could stratify breast cancer patients with a high microvessel density. This study offers the first in vivo evidence of a critical role for intracellular signaling pathways downstream of the ShcA PTB domain, which both positively and negatively regulate tumorigenesis during various stages of breast cancer progression. Cancer Res; 73(14); 4521-32. Ó2013 AACR.

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“…Interestingly, it has recently been shown that SRC is able to phosphorylate SHC at tyrosine residues 239 and 240 in a Ptdlns(4,5)P 2 /PTB dependent manner. 29 Because a RAS-independent 'SRC pathway' has been suggested to culminate in MYC transcription and DNA synthesis in response to activation of the FLT3-related platelet-derived growth factor (PDGF) and M-CSF receptors, 30 it is possible that SRC-related kinases are recruited and activated at the FLT3 juxtamembrane domain and mediate SHC phosphorylation without direct FLT3/SHC interaction. Accordingly, the tyrosine residue (Y590 in the mouse) that should contact the SRC/SRC-like SH2 domain is intact in the FLT3 TM mutant which is still able to phosphorylate SHC.…”

Section: Figurementioning

confidence: 99%

SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor

et al. 1999

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Tyrosine Residues 239 and 240 of Shc Are Phosphatidylinositol 4,5-Bisphosphate-Dependent Phosphorylation Sites by c-Src

Cited by 29 publications

References 23 publications

SU6656, a Selective Src Family Kinase Inhibitor, Used To Probe Growth Factor Signaling

SU6656, a Selective Src Family Kinase Inhibitor, Used To Probe Growth Factor Signaling

The ShcA PTB Domain Functions as a Biological Sensor of Phosphotyrosine Signaling during Breast Cancer Progression

SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor

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