Conformational Basis for SH2-Tyr(P)527 Binding in Src Inactivation

Ayrapetov, Marina K.; Wang, Yuehao; Lin, Xiaofeng; Gu, Xianfeng; Parang, Keykavous; Sun, Gongqin

doi:10.1074/jbc.m604219200

Cited by 25 publications

(23 citation statements)

References 35 publications

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“…Therefore, the ability of PKC to activate Src is likely due to the activity of other proteins that relayed signals from PKC, which in turn direct the activation of Src. The most important regulatory activation of Src is through dephosphorylation of Tyr527 and phosphorylation of Tyr416 (Brown and Cooper, 1996;Cooper et al, 1986;Sicheri et al, 1997;Xu et al, 1997;Ayrapetov et al, 2006). In principle, reduced phosphorylation could result from either decreased Tyr527-directed kinase activity or increased Tyr527-directed phosphatase activity (Thomas and Brugge, 1997;Frame, 2002;Yeatman, 2004;Roskoski, 2005).…”

Section: Discussionmentioning

confidence: 98%

Stimulation by ghrelin of p42/p44 mitogen‐activated protein kinase through the GHS‐R1a receptor: Role of G‐proteins and β‐arrestins

Camiña

Lodeiro

Ischenko

et al. 2007

Journal Cellular Physiology

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Results presented in this study indicate that in human embryonic kidney 293 cells (HEK 293), the ghrelin receptor growth hormone secretagogue receptor type 1a (GHS-R1a) activates the extracellular signal-related kinases 1 and 2 (ERK 1/2) via three pathways. One pathway is mediated by the beta-arrestins 1 and 2, and requires entry of the receptor into a multiprotein complex with the beta-arrestins, Src, Raf-1, and ERK 1/2. A second pathway is G(q/11)-dependent and involves a Ca(2+)-dependent PKC (PKCalpha/beta) and Src. A third pathway is G(i)-dependent and involves phosphoinositide 3-kinase (PI3K), PKCepsilon, and Src. Our current study reveals that G(i/o)- and G(q/11)-proteins are crucially involved in the beta-arrestin-mediated ERK 1/2 activation. These results thus support the view that the beta-arrestins act as both scaffolding proteins and signal transducers in ERK 1/2 activation, as reported for other receptors. The different pathways of ERK 1/2 activation suggest that binding to GHS-R1a activates ERK 1/2 pools at different locations within the cell, and thus probably with different physiological consequences.

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Section: Discussionmentioning

confidence: 98%

Stimulation by ghrelin of p42/p44 mitogen‐activated protein kinase through the GHS‐R1a receptor: Role of G‐proteins and β‐arrestins

Camiña

Lodeiro

Ischenko

et al. 2007

Journal Cellular Physiology

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“…This idea is here further supported by the features of CD99sh, which despite being able to physically interact with c-Src, did not form the complex CD99-caveolin-1-c-Src and thereby did not decrease c-Src kinase activity. The fact that CD99wt, in cooperation with caveolin-1, acts as an allosteric inhibitor of c-Src was also supported by the use of pYEEI, a peptide that has been shown to increase c-Src activity by competing with the c-Src tail (Ayrapetov et al, 2006). By disrupting the intimate interactions between Src and the CD99-caveolin-1 complex, which are necessary to maintain the enzyme in an inhibited conformation, pYEEI restored the Src kinase activity in CD99wt cells and their motile phenotype.…”

Section: Cd99 Isoforms Differently Affect Tumour Metastasis K Scotlanmentioning

confidence: 93%

CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

et al. 2007

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CD99 gene encodes two distinct proteins, produced by alternative splicing of CD99 gene transcript. Full-length CD99 isoform (CD99wt) is formed by an extracellular domain, followed by a transmembrane domain and a 36 amino-acid intracytoplasmic domain, which is partially deleted in the truncated, short form (CD99sh). A differential expression of these two CD99 molecules can lead to distinct functional outcomes in lymphocytes. To investigate the functional effects of CD99 molecules on malignancy, forced overexpression of the two CD99 isoforms was induced in osteosarcoma and prostate cancer cells. The two isoforms exhibited opposite functions: the major form dramatically inhibits anchorage-independent growth, anoikis resistance, migration and metastasis, whereas the CD99sh remarkably favours the phenomena. A mechanistic analysis of CD99-transfected osteosarcoma cells points to involvement of c-Src family kinase activity in regulating CD99 functions in malignancy. Ser168 residue of CD99 plays a pivotal role in the reversion of the malignant phenotype. Our findings highlight the involvement of CD99 in crucial processes of cancer malignancy, serving as a curtain raiser for this, so far neglected molecule. In addition, a dualistic role for the two CD99 isoforms was shown in agreement with what was observed for other cell adhesion molecules.

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“…In particular, we address two open questions with regard to the interactions of the tandem with the rest of the kinase complex. The first issue pertains to the observation that the binding affinity of the wild-type phosphorylated C-tail is per se insufficient to rationalize the degree to which the activity of the enzyme is suppressed by phosphorylation (10,21). Rather, the assembly of the complex appears to rely largely on conformational preferences elsewhere in the protein, which ensure that the SH2 domain and the C-terminal tail become proximal, thus increasing the effective local concentrations of both binding partners.…”

Section: Resultsmentioning

confidence: 99%

On the importance of a funneled energy landscape for the assembly and regulation of multidomain Src tyrosine kinases

Faraldo‐Gómez

Roux

2007

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of signaling pathways in the cell often involves multidomain allosteric enzymes that are able to adopt alternate active or inactive conformations in response to specific stimuli. It is therefore of great interest to elucidate the energetic and structural determinants that govern the conformational plasticity of these proteins. In this study, free-energy computations have been used to address this fundamental question, focusing on one important family of signaling enzymes, the Src tyrosine kinases. Inactivation of these enzymes depends on the formation of an assembly comprising a tandem of SH3 and SH2 modules alongside a catalytic domain. Activation results from the release of the SH3 and SH2 domains, which are then believed to be structurally uncoupled by virtue of a flexible peptide link. In contrast to this view, this analysis shows that inactivation depends critically on the intrinsic propensity of the SH3-SH2 tandem to adopt conformations that are conducive to the assembled inactive state, even when no interactions with the rest of the kinase are possible. This funneling of the available conformational space is encoded within the SH3-SH2 connector, which appears to have evolved to modulate the flexibility of the tandem in solution. To further substantiate this notion, we show how constitutively activating mutations in the SH3-SH2 connector shift the assembly equilibrium toward the disassembled, active state. Based on a similar analysis of several constructs of the kinase complex, we propose that assembly is characterized by the progressive optimization of the protein's conformational energy, with little or no energetic frustration. modular proteins ͉ SH2/SH3 ͉ binding domains ͉ allostery ͉ signaling

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Conformational Basis for SH2-Tyr(P)527 Binding in Src Inactivation

Cited by 25 publications

References 35 publications

Stimulation by ghrelin of p42/p44 mitogen‐activated protein kinase through the GHS‐R1a receptor: Role of G‐proteins and β‐arrestins

Stimulation by ghrelin of p42/p44 mitogen‐activated protein kinase through the GHS‐R1a receptor: Role of G‐proteins and β‐arrestins

CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

On the importance of a funneled energy landscape for the assembly and regulation of multidomain Src tyrosine kinases

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