Tyrosine-protein kinase BTK

NameTyrosine-protein kinase BTK
Synonyms
  • 2.7.10.2
  • Agammaglobulinemia tyrosine kinase
  • AGMX1
  • ATK
  • B-cell progenitor kinase
  • BPK
  • Bruton tyrosine kinase
Gene NameBTK
OrganismHuman
Amino acid sequence
>lcl|BSEQ0002554|Tyrosine-protein kinase BTK
MAAVILESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERGRRGSKKGSIDVEK
ITCVETVVPEKNPPPERQIPRRGEESSEMEQISIIERFPYPFQVVYDEGPLYVFSPTEEL
RKRWIHQLKNVIRYNSDLVQKYHPCFWIDGQYLCCSQTAKNAMGCQILENRNGSLKPGSS
HRKTKKPLPPTPEEDQILKKPLPPEPAAAPVSTSELKKVVALYDYMPMNANDLQLRKGDE
YFILEESNLPWWRARDKNGQEGYIPSNYVTEAEDSIEMYEWYSKHMTRSQAEQLLKQEGK
EGGFIVRDSSKAGKYTVSVFAKSTGDPQGVIRHYVVCSTPQSQYYLAEKHLFSTIPELIN
YHQHNSAGLISRLKYPVSQQNKNAPSTAGLGYGSWEIDPKDLTFLKELGTGQFGVVKYGK
WRGQYDVAIKMIKEGSMSEDEFIEEAKVMMNLSHEKLVQLYGVCTKQRPIFIITEYMANG
CLLNYLREMRHRFQTQQLLEMCKDVCEAMEYLESKQFLHRDLAARNCLVNDQGVVKVSDF
GLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER
FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILDVMDEES
Number of residues659
Molecular Weight76280.71
Theoretical pI7.86
GO Classification
Functions
  • metal ion binding
  • phosphatidylinositol-3,4,5-trisphosphate binding
  • non-membrane spanning protein tyrosine kinase activity
  • protein tyrosine kinase activity
  • identical protein binding
  • ATP binding
Processes
  • intracellular signal transduction
  • toll-like receptor TLR6
  • calcium-mediated signaling
  • positive regulation of B cell differentiation
  • transcription, DNA-templated
  • negative regulation of cytokine production
  • mesoderm development
  • cell maturation
  • regulation of B cell apoptotic process
  • apoptotic signaling pathway
  • regulation of B cell cytokine production
  • I-kappaB kinase/NF-kappaB signaling
  • cell differentiation
  • adaptive immune response
  • innate immune response
  • positive regulation of NF-kappaB transcription factor activity
  • peptidyl-tyrosine autophosphorylation
  • B cell activation
  • peptidyl-tyrosine phosphorylation
  • B cell receptor signaling pathway
  • regulation of cell proliferation
  • MyD88-dependent toll-like receptor signaling pathway
  • Fc-epsilon receptor signaling pathway
  • toll-like receptor 2 signaling pathway
  • toll-like receptor 4 signaling pathway
  • transmembrane receptor protein tyrosine kinase signaling pathway
  • toll-like receptor signaling pathway
  • protein phosphorylation
  • toll-like receptor TLR1
Components
  • plasma membrane
  • membrane raft
  • cytoplasmic vesicle
  • cytosol
  • extrinsic component of cytoplasmic side of plasma membrane
  • cytoplasm
  • intracellular membrane-bounded organelle
  • nucleus
General FunctionProtein tyrosine kinase activity
Specific FunctionNon-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.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID312467
UniProtKB IDQ06187
UniProtKB Entry NameBTK_HUMAN
Cellular LocationCytoplasm
Gene sequence
>lcl|BSEQ0020522|Tyrosine-protein kinase BTK (BTK)
ATGGCCGCAGTGATTCTGGAGAGCATCTTTCTGAAGCGATCCCAACAGAAAAAGAAAACA
TCACCTCTAAACTTCAAGAAGCGCCTGTTTCTCTTGACCGTGCACAAACTCTCCTACTAT
GAGTATGACTTTGAACGTGGGAGAAGAGGCAGTAAGAAGGGTTCAATAGATGTTGAGAAG
ATCACTTGTGTTGAAACAGTGGTTCCTGAAAAAAATCCTCCTCCAGAAAGACAGATTCCG
AGAAGAGGTGAAGAGTCCAGTGAAATGGAGCAAATTTCAATCATTGAAAGGTTCCCTTAT
CCCTTCCAGGTTGTATATGATGAAGGGCCTCTCTACGTCTTCTCCCCAACTGAAGAACTA
AGGAAGCGGTGGATTCACCAGCTCAAAAACGTAATCCGGTACAACAGTGATCTGGTTCAG
AAATATCACCCTTGCTTCTGGATCGATGGGCAGTATCTCTGCTGCTCTCAGACAGCCAAA
AATGCTATGGGCTGCCAAATTTTGGAGAACAGGAATGGAAGCTTAAAACCTGGGAGTTCT
CACCGGAAGACAAAAAAGCCTCTTCCCCCAACGCCTGAGGAGGACCAGATCTTGAAAAAG
CCACTACCGCCTGAGCCAGCAGCAGCACCAGTCTCCACAAGTGAGCTGAAAAAGGTTGTG
GCCCTTTATGATTACATGCCAATGAATGCAAATGATCTACAGCTGCGGAAGGGTGATGAA
TATTTTATCTTGGAGGAAAGCAACTTACCATGGTGGAGAGCACGAGATAAAAATGGGCAG
GAAGGCTACATTCCTAGTAACTATGTCACTGAAGCAGAAGACTCCATAGAAATGTATGAG
TGGTATTCCAAACACATGACTCGGAGTCAGGCTGAGCAACTGCTAAAGCAAGAGGGGAAA
GAAGGAGGTTTCATTGTCAGAGACTCCAGCAAAGCTGGCAAATATACAGTGTCTGTGTTT
GCTAAATCCACAGGGGACCCTCAAGGGGTGATACGTCATTATGTTGTGTGTTCCACACCT
CAGAGCCAGTATTACCTGGCTGAGAAGCACCTTTTCAGCACCATCCCTGAGCTCATTAAC
TACCATCAGCACAACTCTGCAGGACTCATATCCAGGCTCAAATATCCAGTGTCTCAACAA
AACAAGAATGCACCTTCCACTGCAGGCCTGGGATACGGATCATGGGAAATTGATCCAAAG
GACCTGACCTTCTTGAAGGAGCTGGGGACTGGACAATTTGGGGTAGTGAAGTATGGGAAA
TGGAGAGGCCAGTACGACGTGGCCATCAAGATGATCAAAGAAGGCTCCATGTCTGAAGAT
GAATTCATTGAAGAAGCCAAAGTCATGATGAATCTTTCCCATGAGAAGCTGGTGCAGTTG
TATGGCGTCTGCACCAAGCAGCGCCCCATCTTCATCATCACTGAGTACATGGCCAATGGC
TGCCTCCTGAACTACCTGAGGGAGATGCGCCACCGCTTCCAGACTCAGCAGCTGCTAGAG
ATGTGCAAGGATGTCTGTGAAGCCATGGAATACCTGGAGTCAAAGCAGTTCCTTCACCGA
GACCTGGCAGCTCGAAACTGTTTGGTAAACGATCAAGGAGTTGTTAAAGTATCTGATTTC
GGCCTGTCCAGGTATGTCCTGGATGATGAATACACAAGCTCAGTAGGCTCCAAATTTCCA
GTCCGGTGGTCCCCACCGGAAGTCCTGATGTATAGCAAGTTCAGCAGCAAATCTGACATT
TGGGCTTTTGGGGTTTTGATGTGGGAAATTTACTCCCTGGGGAAGATGCCATATGAGAGA
TTTACTAACAGTGAGACTGCTGAACACATTGCCCAAGGCCTACGTCTCTACAGGCCTCAT
CTGGCTTCAGAGAAGGTATATACCATCATGTACAGTTGCTGGCATGAGAAAGCAGATGAG
CGTCCCACTTTCAAAATTCTTCTGAGCAATATTCTAGATGTCATGGATGAAGAATCCTGA
GenBank Gene IDX58957
GeneCard IDNot Available
GenAtlas IDBTK
HGNC IDHGNC:1133
Chromosome LocationX
LocusXq21.33-q22
References
  1. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, Hammarstrom L, Kinnon C, Levinsky R, Bobrow M, et al.: The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993 Jan 21;361(6409):226-33. 8380905
  2. Ohta Y, Haire RN, Litman RT, Fu SM, Nelson RP, Kratz J, Kornfeld SJ, de la Morena M, Good RA, Litman GW: Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):9062-6. 8090769
  3. Rohrer J, Parolini O, Belmont JW, Conley ME, Parolino O [corrected to Parolini O]: The genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia. Immunogenetics. 1994;40(5):319-24. 7927535
  4. Hagemann TL, Chen Y, Rosen FS, Kwan SP: Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia. Hum Mol Genet. 1994 Oct;3(10):1743-9. 7880320
  5. Oeltjen JC, Liu X, Lu J, Allen RC, Muzny D, Belmont JW, Gibbs RA: Sixty-nine kilobases of contiguous human genomic sequence containing the alpha-galactosidase A and Bruton's tyrosine kinase loci. Mamm Genome. 1995 May;6(5):334-8. 7626884
  6. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  7. Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, Platzer M, Howell GR, Burrows C, Bird CP, Frankish A, Lovell FL, Howe KL, Ashurst JL, Fulton RS, Sudbrak R, Wen G, Jones MC, Hurles ME, Andrews TD, Scott CE, Searle S, Ramser J, Whittaker A, Deadman R, Carter NP, Hunt SE, Chen R, Cree A, Gunaratne P, Havlak P, Hodgson A, Metzker ML, Richards S, Scott G, Steffen D, Sodergren E, Wheeler DA, Worley KC, Ainscough R, Ambrose KD, Ansari-Lari MA, Aradhya S, Ashwell RI, Babbage AK, Bagguley CL, Ballabio A, Banerjee R, Barker GE, Barlow KF, Barrett IP, Bates KN, Beare DM, Beasley H, Beasley O, Beck A, Bethel G, Blechschmidt K, Brady N, Bray-Allen S, Bridgeman AM, Brown AJ, Brown MJ, Bonnin D, Bruford EA, Buhay C, Burch P, Burford D, Burgess J, Burrill W, Burton J, Bye JM, Carder C, Carrel L, Chako J, Chapman JC, Chavez D, Chen E, Chen G, Chen Y, Chen Z, Chinault C, Ciccodicola A, Clark SY, Clarke G, Clee CM, Clegg S, Clerc-Blankenburg K, Clifford K, Cobley V, Cole CG, Conquer JS, Corby N, Connor RE, David R, Davies J, Davis C, Davis J, Delgado O, Deshazo D, Dhami P, Ding Y, Dinh H, Dodsworth S, Draper H, Dugan-Rocha S, Dunham A, Dunn M, Durbin KJ, Dutta I, Eades T, Ellwood M, Emery-Cohen A, Errington H, Evans KL, Faulkner L, Francis F, Frankland J, Fraser AE, Galgoczy P, Gilbert J, Gill R, Glockner G, Gregory SG, Gribble S, Griffiths C, Grocock R, Gu Y, Gwilliam R, Hamilton C, Hart EA, Hawes A, Heath PD, Heitmann K, Hennig S, Hernandez J, Hinzmann B, Ho S, Hoffs M, Howden PJ, Huckle EJ, Hume J, Hunt PJ, Hunt AR, Isherwood J, Jacob L, Johnson D, Jones S, de Jong PJ, Joseph SS, Keenan S, Kelly S, Kershaw JK, Khan Z, Kioschis P, Klages S, Knights AJ, Kosiura A, Kovar-Smith C, Laird GK, Langford C, Lawlor S, Leversha M, Lewis L, Liu W, Lloyd C, Lloyd DM, Loulseged H, Loveland JE, Lovell JD, Lozado R, Lu J, Lyne R, Ma J, Maheshwari M, Matthews LH, McDowall J, McLaren S, McMurray A, Meidl P, Meitinger T, Milne S, Miner G, Mistry SL, Morgan M, Morris S, Muller I, Mullikin JC, Nguyen N, Nordsiek G, Nyakatura G, O'Dell CN, Okwuonu G, Palmer S, Pandian R, Parker D, Parrish J, Pasternak S, Patel D, Pearce AV, Pearson DM, Pelan SE, Perez L, Porter KM, Ramsey Y, Reichwald K, Rhodes S, Ridler KA, Schlessinger D, Schueler MG, Sehra HK, Shaw-Smith C, Shen H, Sheridan EM, Shownkeen R, Skuce CD, Smith ML, Sotheran EC, Steingruber HE, Steward CA, Storey R, Swann RM, Swarbreck D, Tabor PE, Taudien S, Taylor T, Teague B, Thomas K, Thorpe A, Timms K, Tracey A, Trevanion S, Tromans AC, d'Urso M, Verduzco D, Villasana D, Waldron L, Wall M, Wang Q, Warren J, Warry GL, Wei X, West A, Whitehead SL, Whiteley MN, Wilkinson JE, Willey DL, Williams G, Williams L, Williamson A, Williamson H, Wilming L, Woodmansey RL, Wray PW, Yen J, Zhang J, Zhou J, Zoghbi H, Zorilla S, Buck D, Reinhardt R, Poustka A, Rosenthal A, Lehrach H, Meindl A, Minx PJ, Hillier LW, Willard HF, Wilson RK, Waterston RH, Rice CM, Vaudin M, Coulson A, Nelson DL, Weinstock G, Sulston JE, Durbin R, Hubbard T, Gibbs RA, Beck S, Rogers J, Bentley DR: The DNA sequence of the human X chromosome. Nature. 2005 Mar 17;434(7031):325-37. 15772651
  8. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  9. Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, Sparkes RS, Kubagawa H, Mohandas T, Quan S, et al.: Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993 Jan 29;72(2):279-90. 8425221
  10. Nore BF, Mattsson PT, Antonsson P, Backesjo CM, Westlund A, Lennartsson J, Hansson H, Low P, Ronnstrand L, Smith CI: Identification of phosphorylation sites within the SH3 domains of Tec family tyrosine kinases. Biochim Biophys Acta. 2003 Feb 21;1645(2):123-32. 12573241
  11. Duriez B, Duquesnoy P, Dastot F, Bougneres P, Amselem S, Goossens M: An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. FEBS Lett. 1994 Jun 13;346(2-3):165-70. 8013627
  12. Vihinen M, Nilsson L, Smith CI: Tec homology (TH) adjacent to the PH domain. FEBS Lett. 1994 Aug 22;350(2-3):263-5. 8070576
  13. Park H, Wahl MI, Afar DE, Turck CW, Rawlings DJ, Tam C, Scharenberg AM, Kinet JP, Witte ON: Regulation of Btk function by a major autophosphorylation site within the SH3 domain. Immunity. 1996 May;4(5):515-25. 8630736
  14. Yang W, Desiderio S: BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):604-9. 9012831
  15. 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: Identification and characterization of a novel SH3-domain binding protein, Sab, which preferentially associates with Bruton's tyrosine kinase (BtK). Biochem Biophys Res Commun. 1998 Apr 17;245(2):337-43. 9571151
  16. Varnai P, Rother KI, Balla T: Phosphatidylinositol 3-kinase-dependent membrane association of the Bruton's tyrosine kinase pleckstrin homology domain visualized in single living cells. J Biol Chem. 1999 Apr 16;274(16):10983-9. 10196179
  17. Yamadori T, Baba Y, Matsushita M, Hashimoto S, Kurosaki M, Kurosaki T, Kishimoto T, Tsukada S: Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3 domain-binding protein. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6341-6. 10339589
  18. Nore BF, Vargas L, Mohamed AJ, Branden LJ, Backesjo CM, Islam TC, Mattsson PT, Hultenby K, Christensson B, Smith CI: Redistribution of Bruton's tyrosine kinase by activation of phosphatidylinositol 3-kinase and Rho-family GTPases. Eur J Immunol. 2000 Jan;30(1):145-54. 10602036
  19. Mohamed AJ, Vargas L, Nore BF, Backesjo CM, Christensson B, Smith CI: Nucleocytoplasmic shuttling of Bruton's tyrosine kinase. J Biol Chem. 2000 Dec 22;275(51):40614-9. 11016936
  20. Kang SW, Wahl MI, Chu J, Kitaura J, Kawakami Y, Kato RM, Tabuchi R, Tarakhovsky A, Kawakami T, Turck CW, Witte ON, Rawlings DJ: PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization. EMBO J. 2001 Oct 15;20(20):5692-702. 11598012
  21. Rodriguez R, Matsuda M, Perisic O, Bravo J, Paul A, Jones NP, Light Y, Swann K, Williams RL, Katan M: Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling. J Biol Chem. 2001 Dec 21;276(51):47982-92. Epub 2001 Oct 17. 11606584
  22. Liu W, Quinto I, Chen X, Palmieri C, Rabin RL, Schwartz OM, Nelson DL, Scala G: Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein. Nat Immunol. 2001 Oct;2(10):939-46. 11577348
  23. Vargas L, Nore BF, Berglof A, Heinonen JE, Mattsson PT, Smith CI, Mohamed AJ: Functional interaction of caveolin-1 with Bruton's tyrosine kinase and Bmx. J Biol Chem. 2002 Mar 15;277(11):9351-7. Epub 2001 Dec 19. 11751885
  24. Guo S, Ferl GZ, Deora R, Riedinger M, Yin S, Kerwin JL, Loo JA, Witte ON: A phosphorylation site in Bruton's tyrosine kinase selectively regulates B cell calcium signaling efficiency by altering phospholipase C-gamma activation. Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14180-5. Epub 2004 Sep 16. 15375214
  25. Yu L, Mohamed AJ, Vargas L, Berglof A, Finn G, Lu KP, Smith CI: Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1. J Biol Chem. 2006 Jun 30;281(26):18201-7. Epub 2006 Apr 27. 16644721
  26. Horwood NJ, Page TH, McDaid JP, Palmer CD, Campbell J, Mahon T, Brennan FM, Webster D, Foxwell BM: Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production. J Immunol. 2006 Mar 15;176(6):3635-41. 16517732
  27. 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. 16738337
  28. Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, Crack PJ, Nicholson SE, Hilton DJ, O'Neill LA, Hertzog PJ: Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol. 2006 Feb;7(2):148-55. Epub 2006 Jan 15. 16415872
  29. Doyle SL, Jefferies CA, Feighery C, O'Neill LA: Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine kinase. J Biol Chem. 2007 Dec 21;282(51):36953-60. Epub 2007 Oct 11. 17932028
  30. Voss M, Lettau M, Janssen O: Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening. BMC Immunol. 2009 Oct 6;10:53. doi: 10.1186/1471-2172-10-53. 19807924
  31. Uckun FM: Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis. Biochem Pharmacol. 1998 Sep 15;56(6):683-91. 9751072
  32. Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, Aints A, Christensson B, Berglof A, Vihinen M, Nore BF, Smith CI: Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009 Mar;228(1):58-73. doi: 10.1111/j.1600-065X.2008.00741.x. 19290921
  33. Oppermann FS, Gnad F, Olsen JV, Hornberger R, Greff Z, Keri G, Mann M, Daub H: Large-scale proteomics analysis of the human kinome. Mol Cell Proteomics. 2009 Jul;8(7):1751-64. doi: 10.1074/mcp.M800588-MCP200. Epub 2009 Apr 15. 19369195
  34. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. 21269460
  35. Eifert C, Wang X, Kokabee L, Kourtidis A, Jain R, Gerdes MJ, Conklin DS: A novel isoform of the B cell tyrosine kinase BTK protects breast cancer cells from apoptosis. Genes Chromosomes Cancer. 2013 Oct;52(10):961-75. doi: 10.1002/gcc.22091. Epub 2013 Aug 3. 23913792
  36. Vaca Jacome AS, Rabilloud T, Schaeffer-Reiss C, Rompais M, Ayoub D, Lane L, Bairoch A, Van Dorsselaer A, Carapito C: N-terminome analysis of the human mitochondrial proteome. Proteomics. 2015 Jul;15(14):2519-24. doi: 10.1002/pmic.201400617. Epub 2015 Jun 8. 25944712
  37. Hyvonen M, Saraste M: Structure of the PH domain and Btk motif from Bruton's tyrosine kinase: molecular explanations for X-linked agammaglobulinaemia. EMBO J. 1997 Jun 16;16(12):3396-404. 9218782
  38. Hansson H, Mattsson PT, Allard P, Haapaniemi P, Vihinen M, Smith CI, Hard T: Solution structure of the SH3 domain from Bruton's tyrosine kinase. Biochemistry. 1998 Mar 3;37(9):2912-24. 9485443
  39. Baraldi E, Djinovic Carugo K, Hyvonen M, Surdo PL, Riley AM, Potter BV, O'Brien R, Ladbury JE, Saraste M: Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate. Structure. 1999 Apr 15;7(4):449-60. 10196129
  40. Tzeng SR, Lou YC, Pai MT, Jain ML, Cheng JW: Solution structure of the human BTK SH3 domain complexed with a proline-rich peptide from p120cbl. J Biomol NMR. 2000 Apr;16(4):303-12. 10826882
  41. Mao C, Zhou M, Uckun FM: Crystal structure of Bruton's tyrosine kinase domain suggests a novel pathway for activation and provides insights into the molecular basis of X-linked agammaglobulinemia. J Biol Chem. 2001 Nov 2;276(44):41435-43. Epub 2001 Aug 29. 11527964
  42. Huang KC, Cheng HT, Pai MT, Tzeng SR, Cheng JW: Solution structure and phosphopeptide binding of the SH2 domain from the human Bruton's tyrosine kinase. J Biomol NMR. 2006 Sep;36(1):73-8. Epub 2006 Sep 13. 16969585
  43. Marcotte DJ, Liu YT, Arduini RM, Hession CA, Miatkowski K, Wildes CP, Cullen PF, Hong V, Hopkins BT, Mertsching E, Jenkins TJ, Romanowski MJ, Baker DP, Silvian LF: Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases. Protein Sci. 2010 Mar;19(3):429-39. doi: 10.1002/pro.321. 20052711
  44. Kuglstatter A, Wong A, Tsing S, Lee SW, Lou Y, Villasenor AG, Bradshaw JM, Shaw D, Barnett JW, Browner MF: Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures. Protein Sci. 2011 Feb;20(2):428-36. doi: 10.1002/pro.575. 21280133
  45. Vihinen M, Iwata T, Kinnon C, Kwan SP, Ochs HD, Vorechovsky I, Smith CI: BTKbase, mutation database for X-linked agammaglobulinemia (XLA). Nucleic Acids Res. 1996 Jan 1;24(1):160-5. 8594569
  46. Vihinen M, Belohradsky BH, Haire RN, Holinski-Feder E, Kwan SP, Lappalainen I, Lehvaslaiho H, Lester T, Meindl A, Ochs HD, Ollila J, Vorechovsky I, Weiss M, Smith CI: BTKbase, mutation database for X-linked agammaglobulinemia (XLA) Nucleic Acids Res. 1997 Jan 1;25(1):166-71. 9016530
  47. Bradley LA, Sweatman AK, Lovering RC, Jones AM, Morgan G, Levinsky RJ, Kinnon C: Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. Hum Mol Genet. 1994 Jan;3(1):79-83. 8162056
  48. de Weers M, Mensink RG, Kraakman ME, Schuurman RK, Hendriks RW: Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice. Hum Mol Genet. 1994 Jan;3(1):161-6. 8162018
  49. Conley ME, Fitch-Hilgenberg ME, Cleveland JL, Parolini O, Rohrer J: Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase. Hum Mol Genet. 1994 Oct;3(10):1751-6. 7849697
  50. Zhu Q, Zhang M, Winkelstein J, Chen SH, Ochs HD: Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families. Hum Mol Genet. 1994 Oct;3(10):1899-900. 7849721
  51. Vihinen M, Vetrie D, Maniar HS, Ochs HD, Zhu Q, Vorechovsky I, Webster AD, Notarangelo LD, Nilsson L, Sowadski JM, et al.: Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12803-7. 7809124
  52. Vihinen M, Zvelebil MJ, Zhu Q, Brooimans RA, Ochs HD, Zegers BJ, Nilsson L, Waterfield MD, Smith CI: Structural basis for pleckstrin homology domain mutations in X-linked agammaglobulinemia. Biochemistry. 1995 Feb 7;34(5):1475-81. 7849006
  53. Vorechovsky I, Vihinen M, de Saint Basile G, Honsova S, Hammarstrom L, Muller S, Nilsson L, Fischer A, Smith CI: DNA-based mutation analysis of Bruton's tyrosine kinase gene in patients with X-linked agammaglobulinaemia. Hum Mol Genet. 1995 Jan;4(1):51-8. 7711734
  54. Jin H, Webster AD, Vihinen M, Sideras P, Vorechovsky I, Hammarstrom L, Bernatowska-Matuszkiewicz E, Smith CI, Bobrow M, Vetrie D: Identification of Btk mutations in 20 unrelated patients with X-linked agammaglobulinaemia (XLA). Hum Mol Genet. 1995 Apr;4(4):693-700. 7633420
  55. Gaspar HB, Bradley LA, Katz F, Lovering RC, Roifman CM, Morgan G, Levinsky RJ, Kinnon C: Mutation analysis in Bruton's tyrosine kinase, the X-linked agammaglobulinaemia gene, including identification of an insertional hotspot. Hum Mol Genet. 1995 Apr;4(4):755-7. 7633429
  56. Vorechovsky I, Luo L, de Saint Basile G, Hammarstrom L, Webster AD, Smith CI: Improved oligonucleotide primer set for molecular diagnosis of X-linked agammaglobulinaemia: predominance of amino acid substitutions in the catalytic domain of Bruton's tyrosine kinase. Hum Mol Genet. 1995 Dec;4(12):2403-5. 8634718
  57. Hagemann TL, Rosen FS, Kwan SP: Characterization of germline mutations of the gene encoding Bruton's tyrosine kinase in families with X-linked agammaglobulinemia. Hum Mutat. 1995;5(4):296-302. 7627183
  58. Ohashi Y, Tsuchiya S, Konno T: A new point mutation involving a highly conserved leucine in the Btk SH2 domain in a family with X linked agammaglobulinaemia. J Med Genet. 1995 Jan;32(1):77-8. 7897635
  59. Schuster V, Seidenspinner S, Kreth HW: Detection of a novel mutation in the SRC homology domain 2 (SH2) of Bruton's tyrosine kinase and direct female carrier evaluation in a family with X-linked agammaglobulinemia. Am J Med Genet. 1996 May 3;63(1):318-22. 8723128
  60. Hashimoto S, Tsukada S, Matsushita M, Miyawaki T, Niida Y, Yachie A, Kobayashi S, Iwata T, Hayakawa H, Matsuoka H, Tsuge I, Yamadori T, Kunikata T, Arai S, Yoshizaki K, Taniguchi N, Kishimoto T: Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. Blood. 1996 Jul 15;88(2):561-73. 8695804
  61. Kobayashi S, Iwata T, Saito M, Iwasaki R, Matsumoto H, Naritaka S, Kono Y, Hayashi Y: Mutations of the Btk gene in 12 unrelated families with X-linked agammaglobulinemia in Japan. Hum Genet. 1996 Apr;97(4):424-30. 8834236
  62. Vihinen M, Nore BF, Mattsson PT, Backesjo CM, Nars M, Koutaniemi S, Watanabe C, Lester T, Jones A, Ochs HD, Smith CI: Missense mutations affecting a conserved cysteine pair in the TH domain of Btk. FEBS Lett. 1997 Aug 18;413(2):205-10. 9280283
  63. Saha BK, Curtis SK, Vogler LB, Vihinen M: Molecular and structural characterization of five novel mutations in the Bruton's tyrosine kinase gene from patients with X-linked agammaglobulinemia. Mol Med. 1997 Jul;3(7):477-85. 9260159
  64. Conley ME, Mathias D, Treadaway J, Minegishi Y, Rohrer J: Mutations in btk in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet. 1998 May;62(5):1034-43. 9545398
  65. Holinski-Feder E, Weiss M, Brandau O, Jedele KB, Nore B, Backesjo CM, Vihinen M, Hubbard SR, Belohradsky BH, Smith CI, Meindl A: Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics. 1998 Feb;101(2):276-84. 9445504
  66. Vihinen M, Kwan SP, Lester T, Ochs HD, Resnick I, Valiaho J, Conley ME, Smith CI: Mutations of the human BTK gene coding for bruton tyrosine kinase in X-linked agammaglobulinemia. Hum Mutat. 1999;13(4):280-5. 10220140
  67. Curtis SK, Hebert MD, Saha BK: Twin carriers of X-linked agammaglobulinemia (XLA) due to germline mutation in the Btk gene. Am J Med Genet. 2000 Jan 31;90(3):229-32. 10678660
  68. Orlandi P, Ritis K, Moschese V, Angelini F, Arvanitidis K, Speletas M, Sideras P, Plebani A, Rossi P: Identification of nine novel mutations in the Bruton's tyrosine kinase gene in X-linked agammaglobulinaemia patients. Hum Mutat. 2000 Jan;15(1):117. 10612838
  69. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR: Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8. 17344846
  70. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, Xue L, Li DH, Steggerda SM, Versele M, Dave SS, Zhang J, Yilmaz AS, Jaglowski SM, Blum KA, Lozanski A, Lozanski G, James DF, Barrientos JC, Lichter P, Stilgenbauer S, Buggy JJ, Chang BY, Johnson AJ, Byrd JC: Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014 Jun 12;370(24):2286-94. doi: 10.1056/NEJMoa1400029. Epub 2014 May 28. 24869598
  71. Furman RR, Cheng S, Lu P, Setty M, Perez AR, Guo A, Racchumi J, Xu G, Wu H, Ma J, Steggerda SM, Coleman M, Leslie C, Wang YL: Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014 Jun 12;370(24):2352-4. doi: 10.1056/NEJMc1402716. Epub 2014 May 28. 24869597
  72. Cheng S, Guo A, Lu P, Ma J, Coleman M, Wang YL: Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia. 2015 Apr;29(4):895-900. doi: 10.1038/leu.2014.263. Epub 2014 Sep 5. 25189416