| Structural highlights
Function
[BLK_MOUSE] Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling. B-cell receptor (BCR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated coreceptors. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. Signaling through BLK plays an important role in transmitting signals through surface immunoglobulins and supports the pro-B to pre-B transition, as well as the signaling for growth arrest and apoptosis downstream of B-cell receptor. Specifically binds and phosphorylates CD79A at 'Tyr-188'and 'Tyr-199', as well as CD79B at 'Tyr-196' and 'Tyr-207'. Phosphorylates also the immunoglobulin G receptor FCGR2. With FYN and LYN, plays an essential role in pre-B-cell receptor (pre-BCR)-mediated NF-kappa-B activation. Contributes also to BTK activation by indirectly stimulating BTK intramolecular autophosphorylation. In pancreatic islets, acts as a modulator of beta-cells function through the up-regulation of PDX1 and NKX6-1 and consequent stimulation of insulin secretion in response to glucose.[1] [2] [3] [4] [5] [6] [7] [8] [9]
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
Signal transduction in B cells is mediated, in part, by the interaction of the cytoplasmic components of the antigen receptor complex and various members of the src family tyrosine kinases. Key to this process appears to be the interaction of the tyrosine kinase SH2 domains with the tyrosine-phosphorylated cytoplasmic domain of Ig-alpha, a disulfide-bonded heterodimeric (with Ig-beta or Ig-gamma) transmembrane protein that noncovalently associates with the antigen receptor immunoglobin chains. In addition to binding to the phosphorylated cytoplasmic domains of Ig-alpha and Ig-beta, blk and fyn(T), two members of the src family kinases, have been shown to bind overlapping but distinct sets of phosphoproteins [Malek & Desiderio (1993) J. Biol. Chem. 268. 22557-22565]. A comparison of their three-dimensional structures may elucidate the apparently subtle differences required for phosphoprotein discrimination. To begin characterizing the blk/fyn/phosphosphoprotein interactions, we have determined the three-dimensional solution structure of the SH2 domain of blk kinase by nuclear magnetic resonance (NMR) spectroscopy. 1H, 13C, and 15N resonances of the SH2 domain of blk kinase were assigned by analysis of multidimensional, double- and triple-resonance NMR experiments. Twenty structures of the blk SH2 domain were refined with the program X-PLOR using a total of 2080 experimentally derived conformational restraints. The structures converged to a root-mean-squared (rms) distance deviation of 0.51 and 0.95 A for the backbone atoms and for the non-hydrogen atoms, respectively. The blk SH2 domain adopts the prototypical SH2 fold. Structurally, blk SH2 is most similar to the crystal structure of the v-src SH2 domain [Waksman et al. (1993) Nature 358.646-653] and superimposes on the crystal structure with an rmsd of 1.52 A for the backbone atoms. The largest deviations occur in the four loops interconnecting beta-strands A-E, which are the least well-defined regions in the NMR structure. Exclusion of these loops lowers this rmsd to 0.82 A. The conformation of the BC loop in the blk SH2 domain is similar to the open conformation in the apo lck SH2 domain, suggesting that, like the lck SH2 domain, the blk SH2 domain may have a gated phosphopeptide binding site. Finally, it is proposed that the amino acid substitution of Lys 88 (blk) for Glu [fyn(T)] is important for the observed differences in specificity between blk and fyn(T) SH2 domains.
The three-dimensional solution structure of the SH2 domain from p55blk kinase.,Metzler WJ, Leiting B, Pryor K, Mueller L, Farmer BT 2nd Biochemistry. 1996 May 21;35(20):6201-11. PMID:8639560[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dymecki SM, Niederhuber JE, Desiderio SV. Specific expression of a tyrosine kinase gene, blk, in B lymphoid cells. Science. 1990 Jan 19;247(4940):332-6. PMID:2404338
- ↑ Yao XR, Scott DW. Antisense oligodeoxynucleotides to the blk tyrosine kinase prevent anti-mu-chain-mediated growth inhibition and apoptosis in a B-cell lymphoma. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7946-50. PMID:7690139
- ↑ Wasserman R, Li YS, Hardy RR. Differential expression of the blk and ret tyrosine kinases during B lineage development is dependent on Ig rearrangement. J Immunol. 1995 Jul 15;155(2):644-51. PMID:7608542
- ↑ Saouaf SJ, Kut SA, Fargnoli J, Rowley RB, Bolen JB, Mahajan S. Reconstitution of the B cell antigen receptor signaling components in COS cells. J Biol Chem. 1995 Nov 10;270(45):27072-8. PMID:7592958
- ↑ Mahajan S, Fargnoli J, Burkhardt AL, Kut SA, Saouaf SJ, Bolen JB. Src family protein tyrosine kinases induce autoactivation of Bruton's tyrosine kinase. Mol Cell Biol. 1995 Oct;15(10):5304-11. PMID:7565679
- ↑ Saouaf SJ, Wolven A, Resh MD, Bolen JB. Palmitylation of Src family tyrosine kinases regulates functional interaction with a B cell substrate. Biochem Biophys Res Commun. 1997 May 19;234(2):325-9. PMID:9177269 doi:http://dx.doi.org/10.1006/bbrc.1997.6638
- ↑ Malek SN, Dordai DI, Reim J, Dintzis H, Desiderio S. Malignant transformation of early lymphoid progenitors in mice expressing an activated Blk tyrosine kinase. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7351-6. PMID:9636152
- ↑ Tretter T, Ross AE, Dordai DI, Desiderio S. Mimicry of pre-B cell receptor signaling by activation of the tyrosine kinase Blk. J Exp Med. 2003 Dec 15;198(12):1863-73. Epub 2003 Dec 8. PMID:14662906 doi:http://dx.doi.org/10.1084/jem.20030729
- ↑ Saijo K, Schmedt C, Su IH, Karasuyama H, Lowell CA, Reth M, Adachi T, Patke A, Santana A, Tarakhovsky A. Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development. Nat Immunol. 2003 Mar;4(3):274-9. Epub 2003 Feb 3. PMID:12563261 doi:http://dx.doi.org/10.1038/ni893
- ↑ Metzler WJ, Leiting B, Pryor K, Mueller L, Farmer BT 2nd. The three-dimensional solution structure of the SH2 domain from p55blk kinase. Biochemistry. 1996 May 21;35(20):6201-11. PMID:8639560 doi:10.1021/bi960157x
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