The human p50csk tyrosine kinase phosphorylates p56lck at Tyr-505 and down regulates its catalytic activity.

Bergman, M; Mustelin, Tomas; Oetken, C; Partanen, Juha; Flint, Nicholas; Amrein, Kurt E.; Autero, Matti; Burn, Paul; Alitalo, Kari

doi:10.1002/j.1460-2075.1992.tb05361.x

Cited by 306 publications

(221 citation statements)

References 49 publications

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“…The contributions of Src kinase were assessed by overexpressed Csk, an approach that relied on the promise that Csk maintains Src kinase in an inhibited state. 26,38,82 The observations that Csk enhances the IL-6 effect (Figs. 5 and 8) and that v-Src phosphorylates gp130 at its SHP-2 binding site (Fig.…”

Section: Discussionmentioning

confidence: 95%

“…The DNAs encoding v-Src (coding region from pGDvSrc Schmitt-Ruppin A Rous sarcoma virus oncogene 36,37 ), human C-terminal Src kinase (Csk) 38 (2.4 kb Sma I fragment, provided by Dr. D.O. Morgan, University of California, San Francisco, CA), rat STAT1␣, STAT3, STAT5, 39 STAT3 ⌬ 55C, 40 mouse STAT4, 41 and human STAT6 42 were subcloned as Not I fragments into pDC vector.…”

Section: Methodsmentioning

confidence: 99%

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Modulation of hepatic acute phase gene expression by epidermal growth factor and src protein tyrosine kinases in murine and human hepatic cells

et al. 1999

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Modulation of hepatic acute phase gene expression by epidermal growth factor and src protein tyrosine kinases in murine and human hepatic cells

et al. 1999

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“…The status of the regulatory tyrosine is maintained both by a kinase, Csk, which phosphorylates it (13), and by a transmembrane phosphatase, CD45, which dephosphorylates it (14). In addition, p56 lck kinase activity is regulated through intramolecular interaction of the SH3 domain with a proline-rich motif in the SH2-kinase linker region.…”

mentioning

confidence: 99%

SOCS-6 Negatively Regulates T Cell Activation through Targeting p56 to Proteasomal Degradation

Choi

Son

Park

et al. 2010

Journal of Biological Chemistry

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The T cell-specific tyrosine kinase, p56 lck , plays crucial roles in T cell receptor (TCR)-mediated T cell activation. Here, we report that SOCS-6 (suppressor of cytokine signaling-6) is a negative regulator of p56 lck . SOCS-6 was identified as a protein binding to the kinase domain of p56 lck through yeast two-hybrid screening. SOCS-6 bound specifically to p56 lck (F505), which mimics the active form of p56 lck , but not to wild type p56 lck . In Jurkat T cells, SOCS-6 binding to p56 lck was detected 1-2 h after TCR stimulation. Confocal microscopy showed that upon APC-T cell conjugation, SOCS-6 was recruited to the immunological synapse and colocalized with the active form of p56 lck . SOCS-6 promoted p56lck ubiquitination and its subsequent targeting to the proteasome. Moreover, SOCS-6 overexpression led to repression of TCR-dependent interleukin-2 promoter activity. These results establish that SOCS-6 acts as a negative regulator of T cell activation by promoting ubiquitin-dependent proteolysis.The T lymphocyte-specific member of the Src-type tyrosine kinase family, p56 lck , plays essential roles in development, antigen-induced T cell activation, and proliferation (1-3). During TCR 4 -mediated T cell activation, p56 lck is activated and transmits a positive signal by interacting with CD4/CD8 (4, 5). Upon engagement of the antigen-major histocompatibility complex with TCR-CD4-CD8 complexes, p56 lck phosphorylates the immunoreceptor tyrosine-based activation motifs of the CD3 -chain and provides the binding site for ZAP-70 tyrosine kinase (6). Subsequent ZAP-70 activation leads to phosphorylation of signaling proteins, including LAT, and amplification of TCR-mediated signaling (7,8). In this process, p56 lck migrates to T cell-APC contact regions known as immunological synapses (IS) and thereby enhances TCR signaling (9, 10). Given the importance of p56 lck function in T cell activation, establishing how p56 lck activity is regulated is essential to understand that activation.The structure of p56 lck is similar to that of other Src family kinases and exhibits the following common domains: N-terminal attachment sites for saturated fatty acid addition, a unique region; an Src homology 3 (SH3) domain; an SH2 domain; a tyrosine kinase domain (SH1); and a C-terminal negative regulatory site, tyrosine 505 (Tyr-505) (11). p56 lck kinase activity is regulated by intramolecular interactions through its regulatory domains and/or phosphorylation (11). For example, phosphorylation of Tyr-394 in the activation loop of the kinase domain increases enzymatic activity, whereas phosphorylation of Tyr-505 renders the enzyme less active. Phosphorylated Tyr-505 interacts with its own SH2 domain, promoting a closed conformation and maintaining the kinase in an inactive state (12). Phenylalanine substitution of the regulatory tyrosine residue (Y505F) results in a constitutively active form of the protein.The status of the regulatory tyrosine is maintained both by a kinase, Csk, which phosphorylates it (13), and by a transmembrane...

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“…Although cAMP has multiple effects on cell metabolism, it has been long known to inhibit T-cell activation (Kammer, 1988), most likely due to activation of PKA (Tasken and Aandahl, 2004) that in turn activates Csk (by phosphorylation of Ser 364 ) which then dampens p56 lck activity (Bergman et al, 1992). (In addition, PKA can also directly phosphorylate p56 lck at Ser 42 which may affect the binding specificity of the adjacent SH2 domain (Winkler et al, 1993).…”

Section: Control Of Csk Activitymentioning

confidence: 99%

Cancer-Induced Signaling Defects in Antitumor T Cells

Frey¹

Tumor-Induced Immune Suppression

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The human p50csk tyrosine kinase phosphorylates p56lck at Tyr-505 and down regulates its catalytic activity.

Cited by 306 publications

References 49 publications

Modulation of hepatic acute phase gene expression by epidermal growth factor and src protein tyrosine kinases in murine and human hepatic cells

Modulation of hepatic acute phase gene expression by epidermal growth factor and src protein tyrosine kinases in murine and human hepatic cells

SOCS-6 Negatively Regulates T Cell Activation through Targeting p56 to Proteasomal Degradation

Cancer-Induced Signaling Defects in Antitumor T Cells

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