4xi2

Structural highlights

Disease

[BTK_MOUSE] Defects in Btk are the cause of murine X-linked immunodeficiency (XID).

Function

[BTK_MOUSE] Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.^{[1] [2] [3] [4] [5] [6]}

See Also

• Tyrosine kinase

References

1. ↑ Kawakami Y, Kitaura J, Hartman SE, Lowell CA, Siraganian RP, Kawakami T. Regulation of protein kinase CbetaI by two protein-tyrosine kinases, Btk and Syk. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7423-8. PMID:10852954 doi:http://dx.doi.org/10.1073/pnas.120175097
2. ↑ Webb CF, Yamashita Y, Ayers N, Evetts S, Paulin Y, Conley ME, Smith EA. The transcription factor Bright associates with Bruton's tyrosine kinase, the defective protein in immunodeficiency disease. J Immunol. 2000 Dec 15;165(12):6956-65. PMID:11120822
3. ↑ Rajaiya J, Nixon JC, Ayers N, Desgranges ZP, Roy AL, Webb CF. Induction of immunoglobulin heavy-chain transcription through the transcription factor Bright requires TFII-I. Mol Cell Biol. 2006 Jun;26(12):4758-68. PMID:16738337 doi:10.1128/MCB.02009-05
4. ↑ Hasan M, Lopez-Herrera G, Blomberg KE, Lindvall JM, Berglof A, Smith CI, Vargas L. Defective Toll-like receptor 9-mediated cytokine production in B cells from Bruton's tyrosine kinase-deficient mice. Immunology. 2008 Feb;123(2):239-49. Epub 2007 Aug 28. PMID:17725607 doi:http://dx.doi.org/10.1111/j.1365-2567.2007.02693.x
5. ↑ Li T, Tsukada S, Satterthwaite A, Havlik MH, Park H, Takatsu K, Witte ON. Activation of Bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain. Immunity. 1995 May;2(5):451-60. PMID:7538439
6. ↑ Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM, Fluckiger AC, Witte ON, Kinet JP. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science. 1996 Feb 9;271(5250):822-5. PMID:8629002
7. ↑ Wang Q, Vogan EM, Nocka LM, Rosen CE, Zorn JA, Harrison SC, Kuriyan J. Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate. Elife. 2015 Feb 20;4. doi: 10.7554/eLife.06074. PMID:25699547 doi:http://dx.doi.org/10.7554/eLife.06074