Basic Information | Overview of PTM Sites | Experimental PTM Sites | Protein-Protein Interactions | Drug and Disease Associations | Related Literatures
Basic Information
Protein Name :  Tyrosine-protein kinase BTK  

UniProtKB / Swiss-Prot ID :  BTK_HUMAN

Gene Name (Synonyms) : 
BTK, AGMX1, ATK, BPK  

Species :  Homo sapiens (Human). 

Subcellular Localization :  Cytoplasm. Cell membrane; Peripheral membrane protein. Nucleus. Note=In steady state, BTK is predominantly cytosolic. Following B-cell receptor (BCR) engagement by antigen, translocates to the plasma membrane through its PH domain. Plasma membrane locali 

Protein Function :  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. 

Protein Sequence MAAVILESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERGRRGSKKGSIDVEKITCVETVVPE...
Predicted Secondary Structure CCHHHHHHHHHHHHHHHCCCCCCCCEEEEEEEECCCEEEEEHHHHHCCCCEECCEEEEEEEEEEEEEECC...
Protein Variant
LocationDescription
11L -> P (in XLA). VAR_006216
12K -> R (in XLA). VAR_006217
14S -> F (in XLA). VAR_006218
19K -> E (in XLA). VAR_008291
25F -> S (in XLA). VAR_006219
27K -> R (in XLA). VAR_008292
28R -> C (in XLA; no effect onphosphorylation of GTF2I).
28R -> H (in XLA; moderate). VAR_006220
28R -> P (in XLA). VAR_006221
33T -> P (in XLA; severe). VAR_006222
39Y -> S (in XLA). VAR_008960
40Y -> C (in XLA). VAR_008294
40Y -> N (in XLA). VAR_008295
61I -> N (in XLA). VAR_008296
64V -> D (in XLA). VAR_008297
64V -> F (in XLA). VAR_006223
82R -> K (in dbSNP:rs56035945). VAR_041676
103Q -> QSVFSSTR (in XLA). VAR_006224
113V -> D (in XLA). VAR_006225
115S -> F (in XLA). VAR_008298
117T -> P (in XLA). VAR_008299
127Q -> H (in XLA). VAR_008300
154C -> S (in XLA). VAR_008301
155C -> G (in XLA). VAR_008302
155C -> R (in XLA). VAR_008303
184T -> P (in XLA). VAR_008304
190P -> K (in a lung large cell carcinomasample; somatic mutation; requires 2
260Missing (in XLA; severe). VAR_006226
288R -> Q (in XLA). VAR_008305
288R -> W (in XLA). VAR_006227
295L -> P (in XLA). VAR_006228
302G -> E (in XLA). VAR_006230
302G -> R (in XLA). VAR_008306
302Missing (in XLA). VAR_006229
307R -> G (in XLA; loss of activity). VAR_006231
307R -> T (in XLA). VAR_008307
308D -> E (in XLA). VAR_008308
319V -> A (in XLA; moderate). VAR_008309
334Y -> S (in XLA). VAR_006232
358L -> F (in XLA). VAR_006233
361Y -> C (in XLA; mild; dbSNP:rs28935478). VAR_006234
362H -> Q (in XLA). VAR_006235
364H -> P (in XLA). VAR_006236
365N -> Y (in XLA). VAR_006237
366S -> F (in XLA). VAR_008310
369L -> F (in XLA). VAR_008311
370I -> M (in XLA). VAR_006238
372R -> G (in XLA). VAR_008312
408L -> P (in XLA; moderate). VAR_006239
414G -> R (in XLA). VAR_008313
418Y -> H (in XLA). VAR_006240
429I -> N (in XLA). VAR_006241
430K -> E (in XLA; loss of phosphorylationof GTF2I).
430K -> R (in XLA). VAR_008314
445E -> D (in XLA). VAR_008315
462G -> D (in XLA). VAR_008316
462G -> V (in XLA). VAR_008317
476Y -> D (in XLA). VAR_006243
477M -> R (in XLA). VAR_006244
502C -> F (in XLA). VAR_006245
502C -> W (in XLA). VAR_006246
506C -> R (in XLA). VAR_006247
506C -> Y (in XLA). VAR_006248
508A -> D (in XLA). VAR_008318
509M -> I (in XLA). VAR_008319
509M -> V (in XLA). VAR_006249
512L -> P (in XLA). VAR_008961
512L -> Q (in XLA). VAR_008962
518L -> R (in XLA). VAR_008320
520R -> Q (in XLA; severe; preventsactivation due to absence of contact
521D -> G (in XLA). VAR_008321
521D -> H (in XLA; severe). VAR_006252
521D -> N (in XLA; severe). VAR_006253
523A -> E (in XLA). VAR_008322
525R -> G (in XLA). VAR_008323
525R -> P (in XLA). VAR_006254
525R -> Q (in XLA; severe; disturbs ATP-binding).
526N -> K (in XLA). VAR_006256
535V -> F (in XLA). VAR_008324
542L -> P (in XLA; growth hormonedeficiency).
544R -> G (in XLA). VAR_008963
544R -> K (in XLA). VAR_006258
559F -> S (in XLA). VAR_008325
562R -> P (in XLA; dbSNP:rs28935176). VAR_006259
562R -> W (in XLA). VAR_006260
563W -> L (in XLA). VAR_008326
567E -> K (in XLA; severe). VAR_006261
578S -> Y (in XLA). VAR_008964
581W -> R (in XLA). VAR_006262
582A -> V (in XLA). VAR_006263
583F -> S (in XLA). VAR_008327
587M -> L (in XLA; mild). VAR_006264
589E -> D (in XLA). VAR_008328
589E -> G (in XLA; moderate; interferes withsubstrate binding).
589E -> K (in XLA). VAR_008965
592S -> P (in XLA). VAR_006267
594G -> E (in XLA; mild; interferes withsubstrate binding).
594G -> R (in XLA). VAR_006269
598Y -> C (in XLA). VAR_006270
607A -> D (in XLA; mild). VAR_006271
613G -> D (in XLA; mild; interferes withsubstrate binding and/or domain
619P -> A (in XLA). VAR_008330
619P -> S (in XLA). VAR_006273
619P -> T (in XLA). VAR_008331
622A -> P (in XLA). VAR_008332
626V -> G (in XLA). VAR_008333
630M -> I (polymorphism, 35%). VAR_006274
630M -> K (in XLA). VAR_006275
630M -> T (in XLA). VAR_008334
633C -> Y (in XLA). VAR_006276
641R -> C (in XLA). VAR_006277
641R -> H (in XLA; severe). VAR_006278
644F -> L (in XLA). VAR_008335
644F -> S (in XLA). VAR_006279
647L -> P (in XLA). VAR_006280
652L -> P (in XLA). VAR_006281
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Overview of Protein Modification Sites with Functional and Structural Information
Accessible Surface Area (ASA)
Pred. Secondary
Real Secondary
Disorder Prediction
Protein Domain
&
Experimental PTM Sites
Predicted PTM Sites
Protein Variant
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Experimental Post-Translational Modification Sites Download
Locations
Modification
Substrate Sites
&
Secondary Structure
Accessible Surface Area (%)
Resource
Reference
Structural Characterization
Orthologous
Protein Cluster
2N-acetylalanine.---MAAVIL
---CCHHHH
15.50UniProtKB
Link-
20Phosphothreonine.QKKKTSPLN
HHCCCCCCC
44.44UniProtKB
Link-
21PhosphoserineKKKTSPLNF
HCCCCCCCC
35.95Phosphositeplus
Link-
21Phosphoserine.KKKTSPLNF
HCCCCCCCC
35.95UniProtKB
Link-
55PhosphoserineSKKGSIDVE
EECCEEEEE
25.21Phosphositeplus
Link-
55Phosphoserine.SKKGSIDVE
EECCEEEEE
25.21UniProtKB
Link-
115Phosphoserine.LYVFSPTEE
EEEEECCHH
22.37UniProtKB
Link-
179PhosphoserineLKPGSSHRK
CCCCCCCCC
31.34Phosphositeplus
Link-
179Phosphoserine.LKPGSSHRK
CCCCCCCCC
31.34UniProtKB
Link-
180PhosphoserineKPGSSHRKT
CCCCCCCCC
32.97Phosphositeplus
Link-
180Phosphoserine (PRKCB)KPGSSHRKT
CCCCCCCCC
32.97HPRD
Link-
180Phosphoserine; by PKC/PRKCB.KPGSSHRKT
CCCCCCCCC
32.97UniProtKB
Link-
191PhosphothreoninePLPPTPEED
CCCCCCCCC
41.20Phosphositeplus
Link-
191Phosphothreonine.PLPPTPEED
CCCCCCCCC
41.20UniProtKB
Link-
223PhosphotyrosineVVALYDYMP
EEEECCCCC
8.69Phosphositeplus
Link
223Phosphotyrosine (ABL1)VVALYDYMP
EEEECCCCC
8.69HPRD
Link
223Phosphotyrosine (Abl;BTK)VVALYDYMP
EEEECCCCC
8.69PhosphoELM
Link
223Phosphotyrosine (BTK)VVALYDYMP
EEEECCCCC
8.69HPRD
Link
223Phosphotyrosine (ITK)VVALYDYMP
EEEECCCCC
8.69HPRD
Link
223Phosphotyrosine (TEC)VVALYDYMP
EEEECCCCC
8.69HPRD
Link
223Phosphotyrosine; by autocatalysis.VVALYDYMP
EEEECCCCC
8.69UniProtKB
Link
225PhosphotyrosineALYDYMPMN
EECCCCCCC
6.91HPRD
Link
225PhosphotyrosineALYDYMPMN
EECCCCCCC
6.91Phosphositeplus
Link
309Phosphoserine.IVRDSSKAG
EEECCCCCC
24.15UniProtKB
Link-
322Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)SVFAKSTGD
EEEECCCCC
36.77Phosphositeplus
Link-
323Phosphoserine.VFAKSTGDP
EEECCCCCC
33.91UniProtKB
Link-
342PhosphoserineSTPQSQYYL
ECCCCCEEE
22.73Phosphositeplus
Link-
342Phosphoserine.STPQSQYYL
ECCCCCEEE
22.73UniProtKB
Link-
344PhosphotyrosinePQSQYYLAE
CCCCEEECC
12.99Phosphositeplus
Link-
361PhosphotyrosineELINYHQHN
HHHHCCCCC
8.89HPRD
Link-
361PhosphotyrosineELINYHQHN
HHHHCCCCC
8.89Phosphositeplus
Link-
361Phosphotyrosine.ELINYHQHN
HHHHCCCCC
8.89UniProtKB
Link-
375PhosphotyrosineSRLKYPVSQ
CCCCCCCCC
17.29Phosphositeplus
Link-
375Phosphotyrosine.SRLKYPVSQ
CCCCCCCCC
17.29UniProtKB
Link-
406Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)LTFLKELGT
EEEEEEEEC
46.86Phosphositeplus
Link-
511PhosphotyrosineEAMEYLESK
HHHHHHHHC
11.59Phosphositeplus
Link-
536Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)QGVVKVSDF
CCEEEEEEC
33.35Phosphositeplus
Link-
543PhosphoserineDFGLSRYVL
ECCEEEEEC
23.19Phosphositeplus
Link-
551PhosphotyrosineLDDEYTSSV
CCCCEEEEE
20.93Phosphositeplus
Link-
551Phosphotyrosine (LYN)LDDEYTSSV
CCCCEEEEE
20.93HPRD
Link-
551Phosphotyrosine (Lyn;BTK)LDDEYTSSV
CCCCEEEEE
20.93PhosphoELM
Link-
551Phosphotyrosine (SYK)LDDEYTSSV
CCCCEEEEE
20.93HPRD
Link-
551Phosphotyrosine; by LYN and SYK.LDDEYTSSV
CCCCEEEEE
20.93UniProtKB
Link-
602PhosphothreonineYERFTNSET
CCCCCHHHH
44.02Phosphositeplus
Link-
602Phosphothreonine.YERFTNSET
CCCCCHHHH
44.02UniProtKB
Link-
604PhosphoserineRFTNSETAE
CCCHHHHHH
33.01Phosphositeplus
Link-
604Phosphoserine.RFTNSETAE
CCCHHHHHH
33.01UniProtKB
Link-
617PhosphotyrosineGLRLYRPHL
CCCCCCCCC
18.70HPRD
Link-
617Phosphotyrosine.GLRLYRPHL
CCCCCCCCC
18.70UniProtKB
Link-
623Phosphoserine.PHLASEKVY
CCCCCHHHH
44.29UniProtKB
Link-
659PhosphoserineMDEES
HCCCC
43.40Phosphositeplus
Link
659Phosphoserine.MDEES
HCCCC
43.40UniProtKB
Link
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Protein-Protein Interactions
      Interacting Protein      
Interaction type
Source ID
      Resource      
      Pubmed ID      
Domain-Domain Interactions
BLNK_HUMANphysical interactionMINT-59470MINT10556826
BLNK_HUMANdirect interactionMINT-3374560MINT16969585
BLNK_HUMANdirect interactionMINT-3374585MINT16969585
BLNK_HUMANphysical interactionMINT-59465MINT10556826
IBTK_HUMANphysical interactionMINT-49793MINT11577348
IBTK_HUMANphysical interactionMINT-49849MINT11577348
IBTK_HUMANphysical interactionMINT-49799MINT11577348
KPCT_HUMANphysical interaction
physical interaction
EBI-704304
EBI-704294
intact11788586
11788586
3BP5_HUMANphysical interaction
physical interaction
physical interaction
physical interaction
EBI-625056
EBI-625046
EBI-624
intact9571151
9571151
9571151
9571151
CD19_HUMANin vitroHPRD:02248HPRD10201980
TNR6_HUMANin vivoHPRD:02248HPRD9751072
EWS_HUMANin vivoHPRD:02248HPRD9201297
HCK_HUMANin vitroHPRD:02248HPRD8058772
JAK1_HUMANin vivoHPRD:02248HPRD9178903
VAV_HUMANin vivoHPRD:02248HPRD9201297
CBL_HUMANin vitroHPRD:02248HPRD10427990
7629518
BMX_HUMANin vitroHPRD:02248HPRD12573241
BTK_HUMANin vitro
in vivo
HPRD:02248HPRD11527964
11231015
12445832
8630736
11598012
8629002
12573241
WASP_HUMANin vitro
in vivo
HPRD:02248HPRD8892607
12235133
10068673
12769846
9742969
PLCG2_HUMANin vitroHPRD:02248HPRD11507089
STA5A_HUMANin vivoHPRD:02248HPRD8617237
7925280
11413148
GTF2I_HUMANin vitro
in vivo
HPRD:02248HPRD9012831
10373551
14623887
9837922
11373296
11313464
11934902
DAPP1_HUMANin vitroHPRD:02248HPRD11524430
TLR8_HUMANyeast 2-hybridHPRD:02248HPRD12724322
MYD88_HUMANin vivoHPRD:02248HPRD12724322
PI51B_HUMANin vitro
in vivo
HPRD:02248HPRD15046600
14614850
TLR4_HUMANyeast 2-hybridHPRD:02248HPRD12724322
PI42B_HUMANin vitro
in vivo
HPRD:02248HPRD15046600
14614850
PI51A_HUMANin vitro
in vivo
HPRD:02248HPRD15046600
14614850
TR10A_HUMANin vivoHPRD:02248HPRD15007095
TLR6_HUMANyeast 2-hybridHPRD:02248HPRD12724322
TLR9_HUMANyeast 2-hybridHPRD:02248HPRD12724322
PI51C_HUMANin vitro
in vivo
HPRD:02248HPRD15046600
14614850
TIRAP_HUMANin vitro
in vivo
HPRD:02248HPRD16439361
16415872
12724322
PI42A_HUMANin vitro
in vivo
HPRD:02248HPRD15046600
14614850
CKLF3_HUMANin vivoHPRD:02248HPRD15087455
KPCZ_HUMANin vitro
in vivo
HPRD:02248HPRD11788586
7522330
KPCT_HUMANin vitro
in vivo
HPRD:02248HPRD11788586
KPCE_HUMANin vitro
in vivo
HPRD:02248HPRD11788586
7522330
KPCA_HUMANin vitro
in vivo
HPRD:02248HPRD11788586
7522330
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Disease Reference
Kegg disease
H00085 Agammaglobulinemias, including the following six diseases: X-linked agammaglobulinemia (Bruton's aga
H00254 Pituitary Dwarfism (PD); Isolated growth hormone deficiency (IGHD); Short Stature and Pituitary Defe
OMIM disease
300755X-linked agammaglobulinemia (XLA)
307200X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD)
Drug Reference
Kegg drug
D10223 Ibrutinib (USAN)
There are no disease associations of PTM sites.
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Related Literatures of Post-Translational Modification
Phosphorylation
ReferencePubMed
"Identification of phosphorylation sites within the SH3 domains of Tecfamily tyrosine kinases.";
Nore B.F., Mattsson P.T., Antonsson P., Backesjo C.-M., Westlund A.,Lennartsson J., Hansson H., Low P., Ronnstrand L., Smith C.I.E.;
Biochim. Biophys. Acta 1645:123-132(2003).
Cited for: PROTEIN SEQUENCE OF 219-235, AND PHOSPHORYLATION AT TYR-223.
"Regulation of Btk function by a major autophosphorylation site withinthe SH3 domain.";
Park H., Wahl M.I., Afar D.E., Turck C.W., Rawlings D.J., Tam C.,Scharenberg A.M., Kinet J.P., Witte O.N.;
Immunity 4:515-525(1996).
Cited for: PHOSPHORYLATION AT TYR-223 AND TYR-551, MUTAGENESIS OF TYR-223, ANDENZYME REGULATION.
"BAP-135, a target for Bruton's tyrosine kinase in response to B cellreceptor engagement.";
Yang W., Desiderio S.;
Proc. Natl. Acad. Sci. U.S.A. 94:604-609(1997).
Cited for: FUNCTION IN PHOSPHORYLATION OF GTF2I, PHOSPHORYLATION AT TYR-223 ANDTYR-551, AND MUTAGENESIS OF GLU-41; PRO-189; TYR-223; TRP-251; ARG-307AND TYR-551.
"PKCbeta modulates antigen receptor signaling via regulation of Btkmembrane localization.";
Kang S.W., Wahl M.I., Chu J., Kitaura J., Kawakami Y., Kato R.M.,Tabuchi R., Tarakhovsky A., Kawakami T., Turck C.W., Witte O.N.,Rawlings D.J.;
EMBO J. 20:5692-5702(2001).
Cited for: PHOSPHORYLATION AT SER-180, AND ENZYME REGULATION.
"A phosphorylation site in Bruton's tyrosine kinase selectivelyregulates B cell calcium signaling efficiency by alteringphospholipase C-gamma activation.";
Guo S., Ferl G.Z., Deora R., Riedinger M., Yin S., Kerwin J.L.,Loo J.A., Witte O.N.;
Proc. Natl. Acad. Sci. U.S.A. 101:14180-14185(2004).
Cited for: PHOSPHORYLATION AT TYR-617 AND SER-623, AND MUTAGENESIS OF TYR-617.
"Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerasePin1.";
Yu L., Mohamed A.J., Vargas L., Berglof A., Finn G., Lu K.P.,Smith C.I.;
J. Biol. Chem. 281:18201-18207(2006).
Cited for: INTERACTION WITH PIN1, PHOSPHORYLATION AT SER-21 AND SER-115, ANDENZYME REGULATION.
"Global survey of phosphotyrosine signaling identifies oncogenickinases in lung cancer.";
Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J.,Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L.,Mitchell J., Wetzel R., Macneill J., Ren J.M., Yuan J.,Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X.,Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J.;
Cell 131:1190-1203(2007).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-551, AND MASSSPECTROMETRY.
"Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosinekinase.";
Doyle S.L., Jefferies C.A., Feighery C., O'Neill L.A.;
J. Biol. Chem. 282:36953-36960(2007).
Cited for: FUNCTION, INTERACTION WITH TLR8 AND TLR9, ENZYME REGULATION, ANDPHOSPHORYLATION AT TYR-223.
"Large-scale proteomics analysis of the human kinome.";
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,Mann M., Daub H.;
Mol. Cell. Proteomics 8:1751-1764(2009).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-20; SER-21; SER-55;SER-179; SER-180; THR-191; TYR-223; SER-309; SER-323; SER-342;TYR-361; TYR-375; TYR-551; THR-602; SER-604 AND SER-659, AND MASSSPECTROMETRY.
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Basic Information | Overview of PTM Sites | Experimental PTM Sites | Protein-Protein Interactions | Drug and Disease Associations | Related Literatures