| 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]
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 kinase p56lck (Lck) is a T-lymphocyte-specific member of the Src family of non-receptor tyrosine kinases. Members of the Src family each contain unique amino-terminal regions, followed by Src-homology domains SH3 and SH2, and a tyrosine kinase domain. SH3 and SH2 domains mediate critical protein interactions in many signal-transducing pathways. They are small, independently folded modules of about 60 and 100 residues, respectively, and they are often but not always found together in the same molecule. Like all nine Src-family kinases (reviewed in ref. 3), Lck is regulated by phosphorylation of a tyrosine in the short C-terminal tail of its catalytic domain. There is evidence that binding of the phosphorylated tail to the SH2 domain inhibits catalytic activity of the kinase domain and that the SH3 and SH2 domains may act together to effect this regulation. Here we report the crystal structures for a fragment of Lck bearing its SH3 and SH2 domains, alone and in complex with a phosphotyrosyl peptide containing the sequence of the Lck C-terminal regulatory tail. The latter complex represents the regulatory apparatus of Lck. The SH3-SH2 fragment forms similar dimers in both crystals, and the tail peptide binds at the intermolecular SH3/SH2 contact. The two structures show how an SH3 domain might recognize a specific target and suggest how dimerization could play a role in regulating Src-family kinases.
Structure of the regulatory domains of the Src-family tyrosine kinase Lck.,Eck MJ, Atwell SK, Shoelson SE, Harrison SC Nature. 1994 Apr 21;368(6473):764-9. PMID:7512222[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, Atwell SK, Shoelson SE, Harrison SC. Structure of the regulatory domains of the Src-family tyrosine kinase Lck. Nature. 1994 Apr 21;368(6473):764-9. PMID:7512222 doi:http://dx.doi.org/10.1038/368764a0
|
