dbPTM

BTK_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	BTK_HUMAN
UniProt AC	Q06187
Protein Name	Tyrosine-protein kinase BTK
Gene Name	BTK
Organism	Homo sapiens (Human).
Sequence Length	659
Subcellular Localization	Cytoplasm. Cell membrane Peripheral membrane protein. Nucleus. 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 localiz
Protein Description	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	MAAVILESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERGRRGSKKGSIDVEKITCVETVVPEKNPPPERQIPRRGEESSEMEQISIIERFPYPFQVVYDEGPLYVFSPTEELRKRWIHQLKNVIRYNSDLVQKYHPCFWIDGQYLCCSQTAKNAMGCQILENRNGSLKPGSSHRKTKKPLPPTPEEDQILKKPLPPEPAAAPVSTSELKKVVALYDYMPMNANDLQLRKGDEYFILEESNLPWWRARDKNGQEGYIPSNYVTEAEDSIEMYEWYSKHMTRSQAEQLLKQEGKEGGFIVRDSSKAGKYTVSVFAKSTGDPQGVIRHYVVCSTPQSQYYLAEKHLFSTIPELINYHQHNSAGLISRLKYPVSQQNKNAPSTAGLGYGSWEIDPKDLTFLKELGTGQFGVVKYGKWRGQYDVAIKMIKEGSMSEDEFIEEAKVMMNLSHEKLVQLYGVCTKQRPIFIITEYMANGCLLNYLREMRHRFQTQQLLEMCKDVCEAMEYLESKQFLHRDLAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYERFTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILDVMDEES

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
2	Acetylation	------MAAVILESI ------CCCHHHHHH	15.50	25944712
20	Phosphorylation	RSQQKKKTSPLNFKK HHHCCCCCCCCCHHH	44.44	30108239
21	Phosphorylation	SQQKKKTSPLNFKKR HHCCCCCCCCCHHHH	35.95	29970186
33	Phosphorylation	KKRLFLLTVHKLSYY HHHHHEEEHHHCCEE	23.78	26074081
38	Phosphorylation	LLTVHKLSYYEYDFE EEEHHHCCEEEECCC	30.39	26074081
39	Phosphorylation	LTVHKLSYYEYDFER EEHHHCCEEEECCCC	15.68	26074081
40	Phosphorylation	TVHKLSYYEYDFERG EHHHCCEEEECCCCC	12.49	26074081
42	Phosphorylation	HKLSYYEYDFERGRR HHCCEEEECCCCCCC	15.15	26074081
51	Phosphorylation	FERGRRGSKKGSIDV CCCCCCCCCCCCCCC	29.40	-
55	Phosphorylation	RRGSKKGSIDVEKIT CCCCCCCCCCCEEEE	25.21	28355574
86	Phosphorylation	IPRRGEESSEMEQIS CCCCCCCCCHHHEEE	27.57	30243723
87	Phosphorylation	PRRGEESSEMEQISI CCCCCCCCHHHEEEE	44.22	30243723
93	Phosphorylation	SSEMEQISIIERFPY CCHHHEEEEHHHCCC	19.74	30243723
115	Phosphorylation	EGPLYVFSPTEELRK CCCEEEECCCHHHHH	22.37	19060867
134	Phosphorylation	QLKNVIRYNSDLVQK HHHHHHHCCHHHHHH	14.11	23917254
174	Phosphorylation	ILENRNGSLKPGSSH CCCCCCCCCCCCCCC	36.45	28348404
179	Phosphorylation	NGSLKPGSSHRKTKK CCCCCCCCCCCCCCC	31.34	20164059
180	Phosphorylation	GSLKPGSSHRKTKKP CCCCCCCCCCCCCCC	32.97	20164059
183	Acetylation	KPGSSHRKTKKPLPP CCCCCCCCCCCCCCC	60.31	7481405
184	Phosphorylation	PGSSHRKTKKPLPPT CCCCCCCCCCCCCCC	44.23	28060719
191	Phosphorylation	TKKPLPPTPEEDQIL CCCCCCCCCHHHCCC	41.20	21082442
223	Phosphorylation	LKKVVALYDYMPMNA HHHHHHHHHCCCCCH	8.69	27155012
225	Phosphorylation	KVVALYDYMPMNAND HHHHHHHCCCCCHHH	6.91	17360941
241	Phosphorylation	QLRKGDEYFILEESN CCCCCCEEEEEECCC	10.72	23532336
263	Phosphorylation	DKNGQEGYIPSNYVT CCCCCCCCCCHHHEE	14.65	-
279	Phosphorylation	AEDSIEMYEWYSKHM CCHHHHHHHHHHHHC	7.19	-
300	Ubiquitination	QLLKQEGKEGGFIVR HHHHHCCCCCCEEEE	53.05	-
309	Phosphorylation	GGFIVRDSSKAGKYT CCEEEECCCCCCCEE	24.15	23898821
310	Phosphorylation	GFIVRDSSKAGKYTV CEEEECCCCCCCEEE	30.71	23898821
315	Phosphorylation	DSSKAGKYTVSVFAK CCCCCCCEEEEEEEE	16.08	23532336
318	Phosphorylation	KAGKYTVSVFAKSTG CCCCEEEEEEEECCC	12.06	24275569
322	Ubiquitination	YTVSVFAKSTGDPQG EEEEEEEECCCCCCC	36.77	21890473
322	Ubiquitination	YTVSVFAKSTGDPQG EEEEEEEECCCCCCC	36.77	21890473
323	Phosphorylation	TVSVFAKSTGDPQGV EEEEEEECCCCCCCE	33.91	28060719
324	Phosphorylation	VSVFAKSTGDPQGVI EEEEEECCCCCCCEE	44.92	28060719
334	Phosphorylation	PQGVIRHYVVCSTPQ CCCEEEEEEEECCCH	5.68	27155012
338	Phosphorylation	IRHYVVCSTPQSQYY EEEEEEECCCHHHHH	31.35	28450419
339	Phosphorylation	RHYVVCSTPQSQYYL EEEEEECCCHHHHHH	21.88	28450419
342	Phosphorylation	VVCSTPQSQYYLAEK EEECCCHHHHHHHHH	22.73	28450419
344	Phosphorylation	CSTPQSQYYLAEKHL ECCCHHHHHHHHHHH	12.99	28450419
345	Phosphorylation	STPQSQYYLAEKHLF CCCHHHHHHHHHHHH	7.56	28450419
361	Phosphorylation	TIPELINYHQHNSAG CHHHHHHHHHCCCCH	8.89	27155012
366	Phosphorylation	INYHQHNSAGLISRL HHHHHCCCCHHHHHC	22.91	28270605
371	Phosphorylation	HNSAGLISRLKYPVS CCCCHHHHHCCCCHH	36.28	28270605
375	Phosphorylation	GLISRLKYPVSQQNK HHHHHCCCCHHHCCC	17.29	22817900
378	Phosphorylation	SRLKYPVSQQNKNAP HHCCCCHHHCCCCCC	22.88	25159151
386	Phosphorylation	QQNKNAPSTAGLGYG HCCCCCCCCCCCCCC	28.60	21964256
387	Phosphorylation	QNKNAPSTAGLGYGS CCCCCCCCCCCCCCC	24.56	21964256
406	Ubiquitination	PKDLTFLKELGTGQF HHHCHHHHHHCCCCE	46.86	21890473
406	Ubiquitination	PKDLTFLKELGTGQF HHHCHHHHHHCCCCE	46.86	21890473
425	Phosphorylation	YGKWRGQYDVAIKMI ECCCCCCEEEEEEEH	18.40	28165663
461	Phosphorylation	HEKLVQLYGVCTKQR HHHHHHHHCHHCCCC	7.16	-
466	Ubiquitination	QLYGVCTKQRPIFII HHHCHHCCCCCEEEE	38.90	-
495	Phosphorylation	EMRHRFQTQQLLEMC HHHHHHHHHHHHHHH	18.64	-
511	Phosphorylation	DVCEAMEYLESKQFL HHHHHHHHHHHHCHH	11.59	22817900
536	Ubiquitination	VNDQGVVKVSDFGLS CCCCCEEEECCCCCC	33.35	2190698
543	Phosphorylation	KVSDFGLSRYVLDDE EECCCCCCEEEECCC	23.19	22817900
551	Phosphorylation	RYVLDDEYTSSVGSK EEEECCCCCCCCCCC	20.93	21482705
552	Phosphorylation	YVLDDEYTSSVGSKF EEECCCCCCCCCCCC	16.69	28060719
553	Phosphorylation	VLDDEYTSSVGSKFP EECCCCCCCCCCCCC	23.33	28176486
558	Ubiquitination	YTSSVGSKFPVRWSP CCCCCCCCCCCCCCC	48.00	-
564	Phosphorylation	SKFPVRWSPPEVLMY CCCCCCCCCCHHHHE	21.73	-
572	Phosphorylation	PPEVLMYSKFSSKSD CCHHHHEECCCCHHH	17.17	24719451
602	Phosphorylation	KMPYERFTNSETAEH CCCHHHCCCHHHHHH	44.02	28450419
604	Phosphorylation	PYERFTNSETAEHIA CHHHCCCHHHHHHHH	33.01	28450419
606	Phosphorylation	ERFTNSETAEHIAQG HHCCCHHHHHHHHHH	36.85	23186163
617	Phosphorylation	IAQGLRLYRPHLASE HHHHHHHHCHHHCCC	18.70	19060867
623	Phosphorylation	LYRPHLASEKVYTIM HHCHHHCCCCEEEEH	44.29	19060867
659	Phosphorylation	LDVMDEES------- HHHHCCCC-------	43.40	7711734

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
51	S	Phosphorylation	Kinase	AKT1	P31749	PSP
180	S	Phosphorylation	Kinase	PRKCB	P05771	Uniprot
223	Y	Phosphorylation	Kinase	ABL1	P00519	PhosphoELM
223	Y	Phosphorylation	Kinase	BTK	Q06187	PSP
223	Y	Phosphorylation	Kinase	BTK	P35991	PSP
223	Y	Phosphorylation	Kinase	ITK	Q08881	PSP
223	Y	Phosphorylation	Kinase	LYN	P07948	PSP
223	Y	Phosphorylation	Kinase	TEC	P42680	PSP
223	Y	Phosphorylation	Kinase	ABL-FAMILY	-	GPS
495	T	Phosphorylation	Kinase	AKT1	P31749	PSP
551	Y	Phosphorylation	Kinase	BTK	Q06187	PSP
551	Y	Phosphorylation	Kinase	SYK	P43405	Uniprot
551	Y	Phosphorylation	Kinase	LYN	P07948	Uniprot
-	K	Ubiquitination	E3 ubiquitin ligase	SMURF1	Q9HCE7	PMID:20804422

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
21	S	Phosphorylation	16644721
Phosphorylation at Ser-21 and Ser-115 creates a binding site for PIN1 at these Ser-Pro motifs, and promotes it's recruitment.
115	S	Phosphorylation	16644721
Phosphorylation at Ser-21 and Ser-115 creates a binding site for PIN1 at these Ser-Pro motifs, and promotes it's recruitment.
180	S	Phosphorylation	11598012
Phosphorylation at Ser-180 by PRKCB, leads in translocation of BTK back to the cytoplasmic fraction.

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Modified Location	Modification	Variant Position (Distance <= 10)	Residue Change	SAP	Related Disease	Reference
Oops, there are no SNP-PTM records of BTK_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
ARI3A_HUMAN	ARID3A	physical	15203319
GTF2I_HUMAN	GTF2I	physical	14623887
KPCB_HUMAN	PRKCB	physical	12679936
CAV1_HUMAN	CAV1	physical	11751885
KPCD1_HUMAN	PRKD1	physical	10561498
KHDR1_HUMAN	KHDRBS1	physical	9201297
VAV_HUMAN	VAV1	physical	9201297
EWS_HUMAN	EWSR1	physical	9201297
WASP_HUMAN	WAS	physical	8892607
KS6B1_HUMAN	RPS6KB1	physical	16640565
KS6B2_HUMAN	RPS6KB2	physical	16640565
FYN_HUMAN	FYN	physical	8058772
LYN_HUMAN	LYN	physical	8058772
HCK_HUMAN	HCK	physical	8058772
CBL_HUMAN	CBL	physical	7629518
IBTK_HUMAN	IBTK	physical	11577348
GTF2I_HUMAN	GTF2I	physical	9012831
BLNK_HUMAN	BLNK	physical	12093870
PLCG2_HUMAN	PLCG2	physical	12093870
CBLB_HUMAN	CBLB	physical	12093870
GNAQ_HUMAN	GNAQ	physical	9770463
BTK_HUMAN	BTK	physical	11527964
BLNK_HUMAN	BLNK	physical	10498607
B2L11_HUMAN	BCL2L11	physical	15096481
GTF2I_HUMAN	GTF2I	physical	15096481
GTF2I_HUMAN	GTF2I	physical	11373296
BTK_HUMAN	BTK	physical	11373296
CBL_HUMAN	CBL	physical	10826882
CBL_HUMAN	CBL	physical	9408950
TLR8_HUMAN	TLR8	physical	12724322
TLR4_HUMAN	TLR4	physical	12724322
TLR6_HUMAN	TLR6	physical	12724322
TLR9_HUMAN	TLR9	physical	12724322
IRAK1_HUMAN	IRAK1	physical	12724322
IBTK_HUMAN	IBTK	physical	18596081
GBB1_HUMAN	GNB1	physical	11698416
BTK_HUMAN	BTK	physical	10427990
CBL_HUMAN	CBL	physical	10427990
WASP_HUMAN	WAS	physical	10427990
KSYK_HUMAN	SYK	physical	10427990
A4_HUMAN	APP	physical	21832049
STA5A_HUMAN	STAT5A	physical	11413148
RS3_HUMAN	RPS3	physical	21080425
AFG32_HUMAN	AFG3L2	physical	21080425
ACTS_HUMAN	ACTA1	physical	21080425
ACTN1_HUMAN	ACTN1	physical	21080425
ATPA_HUMAN	ATP5A1	physical	21080425
ATPB_HUMAN	ATP5B	physical	21080425
COR1C_HUMAN	CORO1C	physical	21080425
DDX3X_HUMAN	DDX3X	physical	21080425
DREB_HUMAN	DBN1	physical	21080425
EF1A2_HUMAN	EEF1A2	physical	21080425
FLNA_HUMAN	FLNA	physical	21080425
G3P_HUMAN	GAPDH	physical	21080425
HORN_HUMAN	HRNR	physical	21080425
K2C5_HUMAN	KRT5	physical	21080425
MYLK2_HUMAN	MYLK2	physical	21080425
NDUS1_HUMAN	NDUFS1	physical	21080425
SFPQ_HUMAN	SFPQ	physical	21080425
SPTA1_HUMAN	SPTA1	physical	21080425
ECHA_HUMAN	HADHA	physical	21080425
TBA4A_HUMAN	TUBA4A	physical	21080425
TBB4B_HUMAN	TUBB4B	physical	21080425
TWF1_HUMAN	TWF1	physical	21080425
UROK_HUMAN	PLAU	physical	21988832
BTK_HUMAN	BTK	physical	8630736
MPP7_HUMAN	MPP7	physical	26344197
BECN1_HUMAN	BECN1	physical	25814554
RT22_HUMAN	MRPS22	physical	25814554
ANR54_HUMAN	ANKRD54	physical	28514442
TTC9C_HUMAN	TTC9C	physical	28514442
M3K4_HUMAN	MAP3K4	physical	28514442
CDC37_HUMAN	CDC37	physical	28514442
HS90A_HUMAN	HSP90AA1	physical	28514442

Drug and Disease Associations

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
300755	X-linked agammaglobulinemia (XLA)
307200	X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD)
Kegg Drug
D10223	Ibrutinib (USAN)
DrugBank
There are no disease associations of PTM sites.

Regulatory Network of BTK_HUMAN

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"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.	19369195 [Abstract]
"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.	16644721 [Abstract]
"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.	15375214 [Abstract]
"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.	11598012 [Abstract]
"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.	17932028 [Abstract]
"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.	18083107 [Abstract]
"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.	9012831 [Abstract]
"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.	8630736 [Abstract]
"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.	12573241 [Abstract]

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