Inactivation of Lck by Csk

Stable Identifier
Reaction [transition]
Homo sapiens
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Protein tyrosine phosphatase CD45 (PTPRC) and CD148 (PTPRJ) have dual function in TCR signaling. They act both in activation as well as inactivation of Src family kinases (SFKs) which are involved in the initiation of TCR signal transduction (Stepanek et al. 2011). The activator role is to dephosphorylate an inhibitory site tyrosine 505 (Y505) at the C-terminal end of Lck, which is needed to enable Lck to an open conformation and expose the activation loop (A-loop) containing the activating tyrosine 394 (Y394) (Xu et al. 1993. McNeill et al. 2007, Zikherman et al. 2010, Stepanek et al. 2011, Salmond et al. 2009).

Lck is a member of the Src family tyrosine kinases and these members have the following domains in common: N-terminal Myristoylation site for saturated fatty acid addition, a unique region, a Src-homology 3 (SH3) domain, an SH2 domain, a tyrosine kinase domain (SH1), and a C-terminal negative regulatory domain. Myristoylation engenders Lck with the ability to attach to cellular membranes. This interaction is mediated by both myristic acid and palmitic acid that are bound to the amino terminal glycine and Cys-3 and/or Cys-5.

The unique region of Lck is thought to be involved in the interaction with the cytoplasmic tails of coreceptors CD4 and CD8. The Lck/CD4 interaction require conserved cysteine motifs: a CxCP motif in CD4 and a CxxC motif in the Lck unique domain. The SH3 and SH2 domains of Lck are involved in intramolecular and intermolecular regulation by mediating protein-protein interactions via poly-proline and phosphotyrosine-specific interactions, respectively.

Lck adopts specific conformation that largely dictate its level of activity. The C-ter tail has an autoinhibitory phosphorylation site (tyr 505). When the Y505 is phosphorylated, Lck adopts a closed conformation, where the pY505 residue creates an intramolecular binding motif for the SH2 domain, effectively inactivating the kinase domain. The inactivating phosphorylation on Y505 is carried out by the Src-specific kinase Csk.

Literature References
PubMed ID Title Journal Year
15489916 Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation

Palacios, EH, Weiss, A

Oncogene 2004
15489910 Structure and regulation of Src family kinases

Boggon, TJ, Eck, MJ

Oncogene 2004
Catalyst Activity

protein tyrosine kinase activity of Csk:p-PAG [plasma membrane]

This event is regulated