Csk

The C-terminal c-Src kinase (Csk) is a 50-kDa cytosolic tyrosine kinase expressed in all examined cell types. Structurally, it resembles the Src family kinases in having SH3, SH2 and kinase domains, but it differs from Src kinases in lacking an N-terminal extension with a myristylation sequence motif, a tyrosine autophosphorylation site, and a C-terminal regulatory tyrosine phosphorylation site.

The physiological function of Csk is to phosphorylate the negative regulatory tyrosine residue in the C-terminus of all Src family kinases. In fact, Csk is probably the only kinase that efficiently phosphorylates this site in vivo, making Csk the general negative regulator of all Src family kinase-mediated events in cells. It is unclear if CSK has any other substrates.

Csk is encoded by an essential gene, the deletion of which is early embryonic lethal in mice due to defects in closure of the neural tube. Transformed embryonic fibroblasts from these animals display a near complete loss of phosphorylation of the C-terminal negative regulatory site in Src family kinases, significantly elevated catalytic activity of all Src like kinases, and constitutive hyperphosphorylation of their substrates.

In contrast to other tyrosine kinases, Csk is apparently not regulated by tyrosine phosphorylation. In fact, the activation loop is shorter than in other kinases and it does not contain any tyrosine residues. Instead, Csk is regulated by phosphorylation of a serine residues, S364, within the larger lobe of its catalytic domain. This site is phosphorylated by cAMP-dependent kinase and results in a several fold activation of Csk. In T cells, agents that elevate cAMP levels (e.g. prostaglandin E2 or membrane-permeable cAMP analogs) caused the phosphorylation of Csk at S364, activated Csk, suppressed Src family kinases, and prevented T cell activation. A phosphorylation site mutant of Csk prevented these responses, suggesting that Csk may be a critical target for cAMP-induced immune suppression.

An important regulator of Csk function is a transmembrane molecule, termed PAG or Cbp, which specifically binds the Csk SH2 domain when phosphorylated. PAG/Cbp is anchored to lipid rafts and is phosphorylated on tyrosine in resting cells, thus anchoring Csk in the subcellular compartment that is enriched in Src family kinases. Upon T cell antigen-receptor triggering, PAG/Cbp is transiently dephosphorylated leading to the dissociation of Csk. This allows lipid raft-located Src family kinases (Lck and Fyn in T cells) to remain active and phosphorylate receptor subunits and other molecules. After a few minutes, PAG/Cbp is again phosphorylated and Csk returns to the lipid rafts. This coincides with the downturn of tyrosine phosphorylation of Src family kinase substrates.

Csk also associates through its SH3 domain with the protein tyrosine phosphatases PTP-PEST and LYP (mouse ortholog is called PEP). As these phosphatases dephosphorylate the positive regulatory tyrosine residue in Src family kinases, it is thought that they synergize with Csk by jointly targeting and suppressing these kinases. Csk has also been shown to bind paxillin and other adapter proteins.

The Csk-homologous kinase (Chk) is 53% identical to Csk and shares the same overall structure of SH3-SH2-kinase domains, but has somewhat longer N- and C-terminal extensions. There are two splice variants of Chk, 52 and 57 kDa, expressed predominantly in brain and hematopoietic cells. Chk expression can be upregulated by several growth factors and mitogen in leukocytes. Chk can phosphorylate Src family kinases in vitro and in breast cancer cells upon recruitment and binding to the ErbB-2/neu receptor kinase.

 

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Family Members Csk Ctk
Other Names Cyl
c-Src tyrosine kinase
lsk
matk
ntk
hyl
batk
Chk
megakaryocyte-associated tyrosine protein kinase
Molecular Weight/
Structural Data
50 kDa
450 aa (human, mouse and rat)
52 kDa and 57 kDa
466/507 aa (human)
465/505 aa (mouse)
Isoforms Not Known
Not Known
Species Yeast
human
mouse
rat
chicken
Human
mouse
rat
Domain Organization 1 SH2 domain
1 SH3 domain
1 protein kinase domain
1 SH2 domain
1 SH3 domain
1 protein kinase domain
Phosphoryation Sites Tyr184
Tyr304
Tyr416
Ser364
Ser501
Tissue Distribution Ubiquitous Brain
Leukocytes
Subcellular Localization Cytosolic Cytosolic
Binding Partners/
Associated Protein
PAG
PEP
PTP-PEST
Paxillin
Paxillin
TrkA
Upstream Activators PKA Not Known
Downstream Activation Src
Lyn
Fyn
Lck
Src
Lyn
Fyn
Lck
Activators Not Known Not Known
In Vivo Substrates C-terminus of Src PTKs (Y527 in Src) Not Known
In Vitro Substrates polyGlu/Tyr C-terminus of Src PTKs
Inhibitors Not Known
Not Known
Selective Inhibitors Not Known
Not Known
Physiological Function Suppression of Src PTKs May play inhibitory role in control of T-cell proliferation
Disease Relevance Not Known
Not Known

 

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References