View source for Bruton's tyrosine kinase

{{Infobox_gene}}

'''Bruton's tyrosine kinase''' (abbreviated '''Btk''' or '''BTK''') also known as '''tyrosine-protein kinase BTK''' is an [[enzyme]] that in humans is encoded by the ''BTK'' [[gene]]. BTK is a [[kinase]] that  plays a crucial role in [[B-cell]] development.

== Function ==

BTK plays a crucial role in [[B cell]] maturation as well as [[mast cell]] activation through the high-affinity [[IgE]] receptor.{{cn|date=November 2018}}

Btk contains a [[PH domain]] that binds [[phosphatidylinositol (3,4,5)-trisphosphate]] (PIP3). PIP3 binding induces Btk to phosphorylate [[phospholipase C]], which in turn hydrolyzes PIP<sub>2</sub>, a [[phosphatidylinositol]], into two second messengers, [[inositol triphosphate]] (IP3) and [[diglyceride|diacylglycerol]] (DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling.{{cn|date=November 2018}}

== Clinical significance ==

Mutations in the BTK gene are implicated in the [[primary immunodeficiency]] disease [[X-linked agammaglobulinemia]] ([[Bruton's agammaglobulinemia]]); sometimes abbreviated to XLA. Patients with XLA have normal pre-B cell populations in their [[bone marrow]] but these cells fail to mature and enter the circulation. The Btk gene is located on the [[X chromosome]].<ref name= IDF>[http://www.immunedisease.com/US/patients/IDF/agamma.html X-Linked Agammaglobulinemia] Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation.</ref> At least 400 [[mutation]]s of the BTK gene have been identified.

=== BTK inhibitors ===
Approved drugs that inhibit BTK :
* [[Ibrutinib]] (PCI-32765), a selective Bruton's tyrosine kinase inhibitor.
*[[Acalabrutinib]], approved in October 2017<ref>https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm583076.htm</ref> for relapsed [[Mantle Cell Lymphoma]]

Various drugs that inhibit BTK are in clinical trials:<ref>[http://seekingalpha.com/article/3753736-astra-signals-a-late-run-on-btk-inhibition Astra Signals A Late Run On BTK Inhibition. Dec 2015]</ref>
* Phase 3:
** [[Acalabrutinib]], for relapsed [[Chronic lymphocytic leukemia|CLL]], 95% overall remission reported.
* Phase 2:
* Phase 1:
** [[ONO-4059]] for [[Non-Hodgkin's Lymphoma]] and/or CLL.<ref name=NCT01659255>{{ClinicalTrialsGov|NCT01659255|ONO-4059 Phase I Dose-escalation Study to Investigate the Safety and Tolerability of ONO-4059 Given as Monotherapy in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma and/or Chronic Lymphocytic Leukaemi}}</ref> Renamed GS-4059 and now in trial NCT02457598.<ref name=Inman2016/>
** [[spebrutinib]] (AVL-292, CC-292) <ref name=NCT01351935>{{ClinicalTrialsGov|NCT01351935|Escalating Dose Study in Subjects With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia}}</ref>
** [[BGB-3111]] for CLL.<ref name=Inman2016>[http://global.onclive.com/conference-coverage/hematology-2016/novel-btk-pi3k-inhibitors-on-horizon-for-relapsed-cll Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016]</ref> It can be taken orally.<ref name=BEIG1606>[http://www.nasdaq.com/press-release/beigene-announces-initiation-of-a-combination-trial-of-the-btk-inhibitor-bgb3111-with-the-pd1-20160629-00939 BeiGene Announces Initiation of a Combination Trial of the BTK Inhibitor BGB-3111 with the PD-1 Antibody BGB-A317. June 2016]</ref>
**HM71224 for [[autoimmune diseases]], under development by [[Hanmi Pharmaceutical]] and [[Eli Lilly and Company|Lilly]] as of 2015<ref>{{cite news|last1=Garde|first1=Damian|title=Lilly inks a $690M deal to get its hands on an autoimmune drug|url=http://www.fiercebiotech.com/r-d/lilly-inks-a-690m-deal-to-get-its-hands-on-an-autoimmune-drug|work=FierceBiotech|date=March 19, 2015|language=en}}</ref>

== Discovery ==

Bruton's [[tyrosine kinase]] was discovered in 1993 and is named for [[Ogden Bruton]], who first described XLA in 1952.<ref name= IDF/>

== Interactions ==

Bruton's tyrosine kinase has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[ARID3A]]<ref name = pmid15203319>{{cite journal | vauthors = Nixon JC, Rajaiya JB, Ayers N, Evetts S, Webb CF | title = The transcription factor, Bright, is not expressed in all human B lymphocyte subpopulations | journal = Cell. Immunol. | volume = 228 | issue = 1 | pages = 42–53  | date = March 2004 | pmid = 15203319 | doi = 10.1016/j.cellimm.2004.03.004 }}</ref> 
* [[B-cell linker|BLNK]],<ref name = pmid12093870/><ref name = pmid10498607>{{cite journal | vauthors = Hashimoto S, Iwamatsu A, Ishiai M, Okawa K, Yamadori T, Matsushita M, Baba Y, Kishimoto T, Kurosaki T, Tsukada S | title = Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK--functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling | journal = Blood | volume = 94 | issue = 7 | pages = 2357–64  | date = October 1999 | pmid = 10498607 | doi =  }}</ref> 
* [[Caveolin 1|CAV1]],<ref name = pmid11751885>{{cite journal | vauthors = Vargas L, Nore BF, Berglof A, Heinonen JE, Mattsson PT, Smith CI, Mohamed AJ | title = Functional interaction of caveolin-1 with Bruton's tyrosine kinase and Bmx | journal = J. Biol. Chem. | volume = 277 | issue = 11 | pages = 9351–7  | date = March 2002 | pmid = 11751885 | doi = 10.1074/jbc.M108537200 }}</ref> 
* [[GNAQ]],<ref name = pmid9770463>{{cite journal | vauthors = Ma YC, Huang XY | title = Identification of the binding site for Gqalpha on its effector Bruton's tyrosine kinase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 21 | pages = 12197–201  | date = October 1998 | pmid = 9770463 | pmc = 22808 | doi = 10.1073/pnas.95.21.12197 }}</ref> 
* [[GTF2I]],<ref name = pmid14623887>{{cite journal | vauthors = Sacristán C, Tussié-Luna MI, Logan SM, Roy AL | title = Mechanism of Bruton's tyrosine kinase-mediated recruitment and regulation of TFII-I | journal = J. Biol. Chem. | volume = 279 | issue = 8 | pages = 7147–58  | date = February 2004 | pmid = 14623887 | doi = 10.1074/jbc.M303724200 }}</ref><ref name = pmid10373551>{{cite journal | vauthors = Novina CD, Kumar S, Bajpai U, Cheriyath V, Zhang K, Pillai S, Wortis HH, Roy AL | title = Regulation of nuclear localization and transcriptional activity of TFII-I by Bruton's tyrosine kinase | journal = Mol. Cell. Biol. | volume = 19 | issue = 7 | pages = 5014–24  | date = July 1999 | pmid = 10373551 | pmc = 84330 | doi =  10.1128/mcb.19.7.5014}}</ref><ref name = pmid9012831>{{cite journal | vauthors = Yang W, Desiderio S | title = BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 2 | pages = 604–9  | date = January 1997 | pmid = 9012831 | pmc = 19560 | doi = 10.1073/pnas.94.2.604 }}</ref>
* [[PLCG2]],<ref name = pmid12093870>{{cite journal | vauthors = Yasuda T, Tezuka T, Maeda A, Inazu T, Yamanashi Y, Gu H, Kurosaki T, Yamamoto T | title = Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells | journal = J. Exp. Med. | volume = 196 | issue = 1 | pages = 51–63  | date = July 2002 | pmid = 12093870 | pmc = 2194016 | doi = 10.1084/jem.20020068 }}</ref><ref name = pmid10981967>{{cite journal | vauthors = Guo B, Kato RM, Garcia-Lloret M, Wahl MI, Rawlings DJ | title = Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex | journal = Immunity | volume = 13 | issue = 2 | pages = 243–53  | date = August 2000 | pmid = 10981967 | doi = 10.1016/s1074-7613(00)00024-8 }}</ref> 
* [[Protein kinase D1|PRKD1]],<ref name = pmid10561498>{{cite journal | vauthors = Johannes FJ, Hausser A, Storz P, Truckenmüller L, Link G, Kawakami T, Pfizenmaier K | title = Bruton's tyrosine kinase (Btk) associates with protein kinase C mu | journal = FEBS Lett. | volume = 461 | issue = 1-2 | pages = 68–72  | date = November 1999 | pmid = 10561498 | doi = 10.1016/S0014-5793(99)01424-6 }}</ref>  and
* [[SH3BP5]].<ref name = pmid9571151>{{cite journal | vauthors = Matsushita M, Yamadori T, Kato S, Takemoto Y, Inazawa J, Baba Y, Hashimoto S, Sekine S, Arai S, Kunikata T, Kurimoto M, Kishimoto T, Tsukada S | title = Identification and characterization of a novel SH3-domain binding protein, Sab, which preferentially associates with Bruton's tyrosine kinase (BtK) | journal = Biochem. Biophys. Res. Commun. | volume = 245 | issue = 2 | pages = 337–43  | date = April 1998 | pmid = 9571151 | doi = 10.1006/bbrc.1998.8420 }}</ref><ref name = pmid10339589>{{cite journal | vauthors = Yamadori T, Baba Y, Matsushita M, Hashimoto S, Kurosaki M, Kurosaki T, Kishimoto T, Tsukada S | title = Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3 domain-binding protein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 11 | pages = 6341–6  | date = May 1999 | pmid = 10339589 | pmc = 26883 | doi = 10.1073/pnas.96.11.6341 }}</ref> 
{{Div col end}}

== See also ==
* [[Ibrutinib]] (PCI-32765)
*[[Acalabrutinib]]
{{Clear}}

== References ==
{{Reflist|35em}}

== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Ochs HD, Aruffo A | title = Advances in X-linked immunodeficiency diseases | journal = Curr. Opin. Pediatr. | volume = 5 | issue = 6 | pages = 684–91 | year = 1993 | pmid = 7907259 | doi = 10.1097/00008480-199312000-00008 }}
* {{cite journal | vauthors = Uckun FM | title = Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis | journal = Biochem. Pharmacol. | volume = 56 | issue = 6 | pages = 683–91 | year = 1998 | pmid = 9751072 | doi = 10.1016/S0006-2952(98)00122-1 }}
* {{cite journal | vauthors = Tsubata T, Wienands J | title = B cell signaling. Introduction | journal = Int. Rev. Immunol. | volume = 20 | issue = 6 | pages = 675–8 | year = 2001 | pmid = 11913944 | doi = 10.3109/08830180109045584 }}
* {{cite journal | vauthors = Etzioni A | title = Novel aspects of hypogammaglobulinemic states | journal = Isr. Med. Assoc. J. | volume = 4 | issue = 4 | pages = 294–7 | year = 2002 | pmid = 12001708 | doi =  }}
* {{cite journal | vauthors = Niiro H, Clark EA | title = Branches of the B cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1 | journal = Immunity | volume = 19 | issue = 5 | pages = 637–40 | year = 2003 | pmid = 14614850 | doi = 10.1016/S1074-7613(03)00303-0 }}
* {{cite journal | vauthors = Carpenter CL | title = Btk-dependent regulation of phosphoinositide synthesis | journal = Biochem. Soc. Trans. | volume = 32 | issue = Pt 2 | pages = 326–9 | year = 2004 | pmid = 15046600 | doi = 10.1042/BST0320326 }}
* {{cite journal | vauthors = Hendriks RW, Kersseboom R | title = Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells | journal = Semin. Immunol. | volume = 18 | issue = 1 | pages = 67–76 | year = 2006 | pmid = 16300960 | doi = 10.1016/j.smim.2005.10.002 }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=xla  GeneReviews/NCBI/NIH/UW entry on X-Linked or Brunton's Agammaglobulinemia]
* {{MeshName|Bruton's+tyrosine+kinase}}
* {{UCSC gene info|BTK}}

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[[Category:Peripheral membrane proteins]]
[[Category:Tyrosine kinases]]