The SH4-Unique-SH3-SH2 domains dictate specificity in signaling that differentiate c-Yes from c-Src

Summy, Justin M.; Qian, Yong; Jiang, Bing-Hua; Guappone-Koay, Anne; Gatesman, Amanda; Shi, Xianglin; Flynn, Daniel C.

doi:10.1242/jcs.00466

Cited by 30 publications

(23 citation statements)

References 56 publications

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“…In Fyn, for example, this region may associate with the cytoplasmic chains of the T-cell receptor via its amino-terminal region (Timson Gauen et al, 1992), but this interaction is weak and not well characterized. Additionally, studies of chimeric Src/Yes proteins show that the Yes unique region cannot substitute for the corresponding region of Src, supporting the notion of distinct interactions and function for this domain (Summy et al, 2003). The autoinhibited conformation of Src…”

Section: Structure Of the Unique Domain Of Lckmentioning

confidence: 76%

Structure and regulation of Src family kinases

2004

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Src family kinases are prototypical modular signaling proteins. Their conserved domain organization includes a myristoylated N-terminal segment followed by SH3, SH2, and tyrosine kinase domains, and a short C-terminal tail. Structural dissection of Src kinases has elucidated the canonical mechanisms of phosphotyrosine recognition by the SH2 domain and proline-motif recognition by the SH3 domain. Crystallographic analysis of nearly intact Src kinases in the autoinhibited state has shown that these protein interaction motifs turn inward and lock the kinase in an inactive conformation via intramolecular interactions. The autoinhibited Src kinase structures reveal a mode of domain assembly used by other tyrosine kinases outside the Src family, including Abl and likely Tec family kinases. Furthermore, they illustrate the underlying regulatory principles that have proven to be general among diverse modular signaling proteins. Although there is considerable structural information available for the autoinhibited conformation of Src kinases, how they may assemble into active signaling complexes with substrates and regulators remains largely unexplored.

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Section: Structure Of the Unique Domain Of Lckmentioning

confidence: 76%

Structure and regulation of Src family kinases

2004

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“…Little is known about specific effects exerted by Yes, although recent studies indicate that the SH4-Unique-SH3-SH2 domains dictate specificity in the signaling of c-Yes and c-Src, respectively (36). Redundant functions of Src and Yes, respectively, are suggested by the finding that c-yes knockout mice display almost no overt phenotype (37).…”

Section: Discussionmentioning

confidence: 99%

The Src Family Kinase Yes Triggers Hyperosmotic Activation of the Epidermal Growth Factor Receptor and CD95

Reinehr

Becker

Höngen

et al. 2004

Journal of Biological Chemistry

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Hyperosmotic exposure of rat hepatocytes triggers epidermal growth factor receptor (EGFR) activation, which results in an activation of the CD95 system and sensitizes the cells toward apoptosis (Reinehr, R., Schliess, F., and Hä ussinger, D. (2003) FASEB J. 17, 731-733). The mechanisms underlying the hyperosmotic EGFR activation were studied. Hyperosmotic exposure (405 mosM) resulted in a rapid activation of the Src kinase family members Yes, Fyn, and Lck. Hyperosmotic Yes, but not Fyn activation, was antioxidant-sensitive and was followed by a rapid Yes/EGFR association. PP-2 abolished the hyperosmotic activation of Fyn and Lck but not activation of Yes and EGFR and their association. However, these latter processes were prevented in the presence of SU6656. SU6656 and antioxidants, but not PP-2 and AG1478, also inhibited the hyperosmotic JNK activation. Cyclic AMP had no effect on hyperosmotic Yes and JNK activation but prevented EGFR/Yes association and EGFR activation in an H89-sensitive way. When the hyperosmolarity-induced Yes-EGFR protein complex started to disappear after 30 min, an association between EGFR and CD95 became apparent, which was followed by CD95 tyrosine phosphorylation and activation. SU6656 but not PP-2 also inhibited EGFR/CD95 association, CD95 tyrosine phosphorylation, CD95 membrane trafficking, and death-inducing signaling complex (DISC) formation. EGFR knockdown had no effect on hyperosmotic Yes activation but prevented CD95 tyrosine phosphorylation, membrane targeting, and DISC formation. Hyperosmotic EGFR and CD95 activation was also largely blunted following Yes knockdown. The data suggest that hyperosmotic signaling triggers an oxidative stress-dependent Yes activation, which is followed by JNK and EGFR activation and subsequent activation of the CD95 system. However, the functional relevance of hyperosmolarity-induced Fyn and Lck activation remains to be elucidated.Changes in liver cell hydration are important regulators of hepatic metabolism, gene expression, and transport across the plasma membrane through activation of osmosensing and osmosignaling pathways (1-6). Hypoosmotic cell swelling involves integrin-dependent osmosensing and osmosignaling via Src kinase and mitogen-activated protein kinases (7, 8), resulting in an inhibition of autophagic proteolysis and stimulation of bile acid excretion (7,8).Little is known about osmosensing and osmosignaling in response to hyperosmotic hepatocyte shrinkage. Apart from effects on metabolism and gene expression (1-6), hyperosmotic hepatocyte shrinkage triggers a rapid translocation of intracellular CD95 to the plasma membrane, which is accompanied by DISC 1 formation and sensitizes hepatocytes toward CD95 ligand (CD95L)-induced apoptosis (9, 10). Hyperosmotic membrane targeting and activation of CD95 involves rapid activation of the epidermal growth factor receptor (EGFR) and of c-Jun-N-terminal kinases (JNK) (10), an association of activated EGFR and CD95, and subsequent CD95 tyrosine phosphorylation by the EGFR tyrosine kinase activ...

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“…All family members also contain an SH4 membrane-targeting region at their N-terminus, is always myristoylated and sometimes palmitoylated prior to membrane localization [117,118]. The SH4 region is followed by an 'unique' domain, which is the only non-conserved region within the kinase family [119]. It contains 50-70 residues which are divergent among family members and also contain a C-terminal regulatory region [119].…”

Section: Src Family Of Kinases (Sfk)mentioning

confidence: 99%

“…The SH4 region is followed by an 'unique' domain, which is the only non-conserved region within the kinase family [119]. It contains 50-70 residues which are divergent among family members and also contain a C-terminal regulatory region [119]. The unique domain is followed by modular SH3 and SH2 domains, a regulatory linker, the catalytic or kinase domain (SH1 domain), and a C-terminal negative regulatory tail.…”

Section: Src Family Of Kinases (Sfk)mentioning

confidence: 99%

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Subramaniam

Shanmugam

Perumal

et al. 2013

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

203

229

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a b s t r a c t a r t i c l e i n f oHepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis.

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The SH4-Unique-SH3-SH2 domains dictate specificity in signaling that differentiate c-Yes from c-Src

Cited by 30 publications

References 56 publications

Structure and regulation of Src family kinases

Structure and regulation of Src family kinases

The Src Family Kinase Yes Triggers Hyperosmotic Activation of the Epidermal Growth Factor Receptor and CD95

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

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