| Structural highlights
Disease
[LCK_HUMAN] Severe combined immunodeficiency due to LCK deficiency. Note=A chromosomal aberration involving LCK is found in leukemias. Translocation t(1;7)(p34;q34) with TCRB.
Function
[LCK_HUMAN] Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosines residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP.[1] [2] [3] [4] [5] [6] [MT_POVHA] Plays a role in transformation by modulating the activities of cellular proteins involved in control of cell proliferation and by acting as a functional homolog of an activated tyrosine kinase-associated growth-factor receptor. Recruits upon association with Ppp2/PP2A the Src tyrosine kinase component Fyn, thereby activating its kinase activity. In turn, MT becomes phosphorylated and mediates signal transduction pathways leading to cell cycle progression and cell division. MT plays also a role in regulation of early and late gene expression as well as viral DNA replication (By similarity).
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The Src homology-2 (SH2) domains are modules of about 100 amino-acid residues that are found in many intracellular signal-transduction proteins. They bind phosphotyrosine-containing sequences with high affinity and specificity, recognizing phosphotyrosine in the context of the immediately adjacent polypeptide sequence. The protein p56lck (Lck) is a Src-like, lymphocyte-specific tyrosine kinase. A phosphopeptide library screen has recently been used to deduce an 'optimal' binding sequence for the Lck SH2 domain. There is selectivity for the residues Glu, Glu and Ile in the three positions C-terminal to the phosphotyrosine. An 11-residue phosphopeptide derived from the hamster polyoma middle-T antigen, EPQpYEEIPIYL, binds with an approximately 1 nM dissociation constant to the Lck SH2 (ref. 17), an affinity equivalent to that of the tightest known SH2-phosphopeptide complex. We report here the high-resolution crystallographic analysis of the Lck SH2 domain in complex with this phosphopeptide. Recent crystallographically derived structures of the Src SH2 domain in complex with low-affinity peptides, which do not contain the EEI consensus, and NMR-derived structures of unliganded Abl (ref. 19) and p85 (ref. 20) SH2 domains have revealed the conserved fold of the SH2 domain and the properties of a phosphotyrosine binding pocket. Our high-affinity complex shows the presence of a second pocket for the residue (pY + 3) three positions C-terminal to the phosphotyrosine (pY). The peptide is anchored by insertion of the pY and pY + 3 side chains into their pockets and by a network of hydrogen bonds to the peptide main chain. In the low-affinity phosphopeptide/Src complexes, the pY + 3 residues do not insert into the homologous binding pocket and the peptide main chain remains displaced from the surface of the domain.
Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck.,Eck MJ, Shoelson SE, Harrison SC Nature. 1993 Mar 4;362(6415):87-91. PMID:7680435[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gelkop S, Gish GD, Babichev Y, Pawson T, Isakov N. T cell activation-induced CrkII binding to the Zap70 protein tyrosine kinase is mediated by Lck-dependent phosphorylation of Zap70 tyrosine 315. J Immunol. 2005 Dec 15;175(12):8123-32. PMID:16339550
- ↑ Mason LH, Willette-Brown J, Taylor LS, McVicar DW. Regulation of Ly49D/DAP12 signal transduction by Src-family kinases and CD45. J Immunol. 2006 Jun 1;176(11):6615-23. PMID:16709819
- ↑ Goh YM, Cinghu S, Hong ET, Lee YS, Kim JH, Jang JW, Li YH, Chi XZ, Lee KS, Wee H, Ito Y, Oh BC, Bae SC. Src kinase phosphorylates RUNX3 at tyrosine residues and localizes the protein in the cytoplasm. J Biol Chem. 2010 Mar 26;285(13):10122-9. doi: 10.1074/jbc.M109.071381. Epub 2010, Jan 25. PMID:20100835 doi:10.1074/jbc.M109.071381
- ↑ Collins M, Tremblay M, Chapman N, Curtiss M, Rothman PB, Houtman JC. The T cell receptor-mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems. J Leukoc Biol. 2009 Dec 22. PMID:20028775 doi:jlb.0409227
- ↑ Wang H, Zeng X, Fan Z, Lim B. RhoH modulates pre-TCR and TCR signalling by regulating LCK. Cell Signal. 2011 Jan;23(1):249-58. doi: 10.1016/j.cellsig.2010.09.009. Epub 2010, Sep 16. PMID:20851766 doi:10.1016/j.cellsig.2010.09.009
- ↑ Scales TM, Derkinderen P, Leung KY, Byers HL, Ward MA, Price C, Bird IN, Perera T, Kellie S, Williamson R, Anderton BH, Reynolds CH. Tyrosine phosphorylation of tau by the SRC family kinases lck and fyn. Mol Neurodegener. 2011 Jan 26;6:12. doi: 10.1186/1750-1326-6-12. PMID:21269457 doi:10.1186/1750-1326-6-12
- ↑ Eck MJ, Shoelson SE, Harrison SC. Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck. Nature. 1993 Mar 4;362(6415):87-91. PMID:7680435 doi:http://dx.doi.org/10.1038/362087a0
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