Detection of a Physical and Functional Interaction between Csk and Lck Which Involves the SH2 Domain of Csk and Is Mediated by Autophosphorylation of Lck on Tyrosine 394

Bougeret, Cécile; Delaunay, Thierry; Romero, Fráncisco; Jullien, Pascale; Sabe, Hisataka; Hanafusa, Hidesaburô; Bénarous, Richard; Fischer, Siegmund

doi:10.1074/jbc.271.13.7465

Cited by 34 publications

(24 citation statements)

References 52 publications

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“…In contrast, Bougeret et al [46] recently reported that C-terminal phosphorylation of Lck by CSK is enhanced by interactions between autophosphorylated Tyr395 of Lck and the SH2 domain of CSK. Such an interaction, however, does not seem to occur between another autophosphorylated Src kinases, c-Fgr, and CSK [46]. Neither myristoylation nor the unique domain of Src kinase, moreover, seem to be necessary for phosphorylation by CSK [44].…”

Section: Discussionmentioning

confidence: 86%

“…The same apparently applies to the SH2 and SH3 domains of CSK, considering that they are required for the in vivo regulation of Src kinases, but not for the in vitro phosphorylation of the C-terminal tyrosine residue [16,[43][44][45]. In contrast, Bougeret et al [46] recently reported that C-terminal phosphorylation of Lck by CSK is enhanced by interactions between autophosphorylated Tyr395 of Lck and the SH2 domain of CSK. Such an interaction, however, does not seem to occur between another autophosphorylated Src kinases, c-Fgr, and CSK [46].…”

Section: Discussionmentioning

confidence: 99%

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Sequence Specificity of C‐Terminal Src Kinase (Csk)

Ruzzene

Songyang

Marin

et al. 1997

European Journal of Biochemistry

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An eicosapeptide encompassing the C-terminal tail of c-Src (Tyr527) which is conserved in most Srcrelated protein kinases, is phosphorylated by C-terminal Src kinase (CSK) and by the two Src-related protein kinases c-Fgr and Lyn, with similar kinetic constants. Two related peptides reproducing the Cterminal segments of c-Src mutants defective in CSK phosphorylation [MacAuley, A., Okada, M., Nada, S., Nakagawa, H. & Cooper, J. A. (1993) Oncogene 8,117-1241 AFLEDSCTGTEPLYQBGENL (mutant number 28) and AFLEDIJITGTKPQYHPGENL (mutant number 29), proved a better and a much worse substrates, respectively than the wild-type peptide, with either CSK or the two Src kinases. By changing individual residues in the best peptide substrate, it was shown that the main element responsible for its improved phosphorylation is leucine at position -1 (instead of glutamine), while lysine at position -3 (instead of glutamate) has a detrimental effect, possibly accounting for the negligible phosphorylation of peptide derived from mutant number 29. By contrast to most peptide substrates, including the Src C-terminal peptides, which exhibit relatively high K,, values, a polyoma-virus-middle-T-antigen-(mT)-derived peptide with tyrosine embedded in a highly hydrophobic sequence (EEEPQFEEIPIYLELLP) exhibits with CSK a quite low K, value (63 pM). Consistent with this, the optimal sequence selected by CSK in an oriented peptide library is XXXIYMFFF. This is different from sequences selected by Lyn (DEEIYEELX) and c-Fgr (XEEIYGIFF), although they all share a high selection for a hydrophobic residue at n-1. In sharp contrast, T P K I I B I P~~"~, related to the catalytic domain of p72'kk, selects acidic residues at nearly all positions, n-1 included.These data support the notion that the features determining the specific phosphorylation of the Cterminal tyrosine residue of Src do not reside in the primary structure surrounding the target tyrosine. They also show that this site does not entirely fulfil the optimal consensus sequence recognized by CSK, disclosing the possibility that as yet unrecognized CSK targets structurally unrelated to the C-terminal tyrosine residue of Src kinases may exist.Keywords: protein-tyrosine kinase; C-terminal Src kinase ; c-Fgr ; Lyn; specificity.The C-terminal Src kinase (CSK) is a cytoplasmic protein tyrosine kinase which specifically phosphorylates Src-family kinases at their C-terminal tyrosine residue (equivalent to Tyr527 in c-Src), which is a down-regulation site [I, 21. CSK is, therefore, responsible for inhibiting the Tyr kinase activity of members of the Src family by inducing a locked conformation that results from the intramolecular interaction between the C-terminal tyrosine residue phosphorylated by CSK and the Src homology 2 (SH2) domain of the Src kinase 13-61, CSK is expressed in most tissues, while a related kinase with high sequence similarity, recently cloned with different names, megacaryocyte-associated tyrosine kinase (MATK), Ntk, Ctk, Batk, Lsk and HYL, [7 -121 displays a more restricted exp...

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Sequence Specificity of C‐Terminal Src Kinase (Csk)

Ruzzene

Songyang

Marin

et al. 1997

European Journal of Biochemistry

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“…Previous mutational and functional analyses suggest that several regions/residues on Lck could mediate either a direct Lck-Fyn interaction or interactions with intermediate molecule(s) as follows: the unique domain (55)(56)(57) and the SH2 (58) and SH3 (59) domains; the proline-mediated PPII conformation of the linker region (8); and the kinase domain (60,61) or specific residues within the C terminus (17,62). Toward determining which of these sequences might be involved in supporting Y505F Lck-Fyn complex formation, mutants with disabled function of each of these individual domains, and the last five amino acid truncated at the C terminus, were prepared on Y505F Lck cDNA template by site-directed mutagenesis.…”

Section: Panel) Lck-fyn Complex Formation Is Confined To Lipid Raftsmentioning

confidence: 99%

Lck-dependent Fyn Activation Requires C Terminus-dependent Targeting of Kinase-active Lck to Lipid Rafts

Filipp

Moemeni

Ferzoco

et al. 2008

Journal of Biological Chemistry

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Two Src family tyrosine kinases, Lck and Fyn, provide critical functions that predicate the generation of the most proximal signals emanating from the antigen receptor complex in T cells (1, 2). Lck-and Fyn-dependent phosphorylation of many cellular substrates is readily detectable within seconds after T cell receptor engagement (3), and the provision of catalytic activity requires an intact molecular structure (4) and post-translational lipid modifications of these kinases (5-7).Similar to other Src family kinases, Lck and Fyn contain a short N-terminal lipid-modified region, a unique domain, Src homology 3 (SH3) 3 and SH2 domains, a linker region, a catalytic domain, and a C-terminal tail involved in negative regulation of function (8). Biochemical and crystallographic studies revealed that kinase activity is regulated through reversible phosphorylation of two key tyrosine residues. Specifically, the negative regulatory Tyr 505 and Tyr 528 on Lck and Fyn, respectively, and the positive regulatory Tyr 394 and Tyr 417 of Lck and Fyn, respectively, are positioned within the activation loops of their respective kinase domains (9 -12). As Lck and Fyn can be phosphorylated on either of these two regulatory tyrosine residues, the activation of Src kinases is modeled as a sequential two-step mechanism, which allows transitions between three functionally different states (4, 13). The inactive, autoinhibitory conformation is supported in large part by 2-week intra-molecular interactions formed between the SH2 domain and the phosphorylated C-terminal tyrosine and the SH3 domain and the linker region, which cooperatively contribute to down-regulate the kinase activity. CD45-mediated dephosphorylation of the C-terminal phosphotyrosine results in an "open" structure and an active conformation of the kinase domain (14). This initial step of kinase activation can be counteracted by action of the C-terminal Src kinase (Csk) (15, 16). In the second step, full kinase activity is achieved upon phosphorylation of the positive regulatory tyrosine in the activation loop (17).Although not accounting for all possible activation scenarios, this simplified model highlights the important difference between the two activation steps of Lck and Fyn kinases. The initial transition from "closed" to open conformation is con-

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“…CSK appears to translocate to subcellular sites where its activity is probably required for normal regulation of Src-family kinases (Howell and Cooper, 1994). A number of CSK binding proteins have been identi®ed that may play an important role in membrane localization of CSK, and include GTPase-activating protein (GAP)-associated p62 (p62dok) (Neet and Hunter, 1995;Yamanashi and Baltimore, 1997;Carpino et al, 1997) and the Src-family member Lck (Bougeret et al, 1996).…”

Section: Ptp1b and Other Ptps That Might Target C-srcmentioning

confidence: 99%

Selected glimpses into the activation and function of Src kinase

2000

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Since the discovery of the v-src and c-src genes and their products, much progress has been made in the elucidation of the structure, regulation, localization, and function of the Src protein. Src is a non-receptor protein tyrosine kinase that transduces signals that are involved in the control of a variety of cellular processes such as proliferation, di erentiation, motility, and adhesion. Src is normally maintained in an inactive state, but can be activated transiently during cellular events such as mitosis, or constitutively by abnormal events such as mutation (i.e. v-Src and some human cancers). Activation of Src occurs as a result of disruption of the negative regulatory processes that normally suppress Src activity, and understanding the various mechanisms behind Src activation has been a target of intense study. Src associates with cellular membranes, in particular the plasma membrane, and endosomal membranes. Studies indicate that the di erent subcellular localizations of Src could be important for the regulation of speci®c cellular processes such as mitogenesis, cytoskeletal organization, and/or membrane tra cking. This review will discuss the history behind the discovery and initial characterization of Src and the regulatory mechanisms of Src activation, in particular, regulation by modi®cation of the carboxyterminal regulatory tyrosine by phosphatases and kinases. Its focus will then turn to the di erent subcellular localizations of Src and the possible roles of nuclear and perinuclear targets of Src. Finally, a brief section will review some of our present knowledge regarding Src involvement in human cancers. Oncogene (2000) 19, 5620 ± 5635.

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Detection of a Physical and Functional Interaction between Csk and Lck Which Involves the SH2 Domain of Csk and Is Mediated by Autophosphorylation of Lck on Tyrosine 394

Cited by 34 publications

References 52 publications

Sequence Specificity of C‐Terminal Src Kinase (Csk)

Sequence Specificity of C‐Terminal Src Kinase (Csk)

Lck-dependent Fyn Activation Requires C Terminus-dependent Targeting of Kinase-active Lck to Lipid Rafts

Selected glimpses into the activation and function of Src kinase

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