dbPTM

KSYK_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	KSYK_HUMAN
UniProt AC	P43405
Protein Name	Tyrosine-protein kinase SYK
Gene Name	SYK
Organism	Homo sapiens (Human).
Sequence Length	635
Subcellular Localization	Cell membrane . Cytoplasm, cytosol .
Protein Description	Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response (By similarity)..
Protein Sequence	MASSGMADSANHLPFFFGNITREEAEDYLVQGGMSDGLYLLRQSRNYLGGFALSVAHGRKAHHYTIERELNGTYAIAGGRTHASPADLCHYHSQESDGLVCLLKKPFNRPQGVQPKTGPFEDLKENLIREYVKQTWNLQGQALEQAIISQKPQLEKLIATTAHEKMPWFHGKISREESEQIVLIGSKTNGKFLIRARDNNGSYALCLLHEGKVLHYRIDKDKTGKLSIPEGKKFDTLWQLVEHYSYKADGLLRVLTVPCQKIGTQGNVNFGGRPQLPGSHPATWSAGGIISRIKSYSFPKPGHRKSSPAQGNRQESTVSFNPYEPELAPWAADKGPQREALPMDTEVYESPYADPEEIRPKEVYLDRKLLTLEDKELGSGNFGTVKKGYYQMKKVVKTVAVKILKNEANDPALKDELLAEANVMQQLDNPYIVRMIGICEAESWMLVMEMAELGPLNKYLQQNRHVKDKNIIELVHQVSMGMKYLEESNFVHRDLAARNVLLVTQHYAKISDFGLSKALRADENYYKAQTHGKWPVKWYAPECINYYKFSSKSDVWSFGVLMWEAFSYGQKPYRGMKGSEVTAMLEKGERMGCPAGCPREMYDLMNLCWTYDVENRPGFAAVELRLRNYYYDVVN

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
3	Phosphorylation	-----MASSGMADSA -----CCCCCCCCCC	26.57	26503514
4	Phosphorylation	----MASSGMADSAN ----CCCCCCCCCCC	24.05	26503514
28	Phosphorylation	TREEAEDYLVQGGMS CHHHHHHHHHHCCCC	10.57	21469132
35	Phosphorylation	YLVQGGMSDGLYLLR HHHHCCCCHHHHHHH	31.62	29083192
39	Phosphorylation	GGMSDGLYLLRQSRN CCCCHHHHHHHHCCC	14.82	29083192
44	Phosphorylation	GLYLLRQSRNYLGGF HHHHHHHCCCCCCCE	18.96	21469132
47	Phosphorylation	LLRQSRNYLGGFALS HHHHCCCCCCCEEEE	12.96	22322096
54	Phosphorylation	YLGGFALSVAHGRKA CCCCEEEEHHCCCCC	17.52	29438985
60	Ubiquitination	LSVAHGRKAHHYTIE EEHHCCCCCCEEEEE	57.58	-
73	Phosphorylation	IERELNGTYAIAGGR EEEECCCCEEECCCC	14.54	28857561
74	Phosphorylation	ERELNGTYAIAGGRT EEECCCCEEECCCCC	9.45	27259358
91	Phosphorylation	SPADLCHYHSQESDG CHHHHCCCCCCCCCC	11.36	27642862
93	Phosphorylation	ADLCHYHSQESDGLV HHHCCCCCCCCCCEE	28.60	24247654
105	Acetylation	GLVCLLKKPFNRPQG CEEEEEECCCCCCCC	55.61	11792735
116	Acetylation	RPQGVQPKTGPFEDL CCCCCCCCCCCHHHH	49.36	11792747
117	O-linked_Glycosylation	PQGVQPKTGPFEDLK CCCCCCCCCCHHHHH	57.69	30379171
131	Phosphorylation	KENLIREYVKQTWNL HHHHHHHHHHHHHCC	11.78	28450419
161	Phosphorylation	LEKLIATTAHEKMPW HHHHHHHCHHHHCCC	19.59	19413330
178	Phosphorylation	GKISREESEQIVLIG CCCCHHHCCEEEEEE	30.01	-
202	Phosphorylation	RARDNNGSYALCLLH EEECCCCCEEEEEEE	14.89	28152594
203	Phosphorylation	ARDNNGSYALCLLHE EECCCCCEEEEEEEC	12.65	28152594
236	Phosphorylation	PEGKKFDTLWQLVEH CCCCCCHHHHHHHHH	32.78	27251275
244	Phosphorylation	LWQLVEHYSYKADGL HHHHHHHHCCCCCCC	10.53	28450419
245	Phosphorylation	WQLVEHYSYKADGLL HHHHHHHCCCCCCCE	23.28	28450419
246	Phosphorylation	QLVEHYSYKADGLLR HHHHHHCCCCCCCEE	11.74	28450419
256	Phosphorylation	DGLLRVLTVPCQKIG CCCEEEEEEECCCCC	21.39	21469132
283 (in isoform 2)	Phosphorylation	-	25.14	28348404
284 (in isoform 2)	Phosphorylation	-	6.57	28348404
295	Phosphorylation	GIISRIKSYSFPKPG CHHHHHHHCCCCCCC	24.52	22322096
296	Phosphorylation	IISRIKSYSFPKPGH HHHHHHHCCCCCCCC	14.88	22322096
297	Phosphorylation	ISRIKSYSFPKPGHR HHHHHHCCCCCCCCC	42.01	23401153
306	Phosphorylation	PKPGHRKSSPAQGNR CCCCCCCCCCCCCCC	41.32	29052541
307	Phosphorylation	KPGHRKSSPAQGNRQ CCCCCCCCCCCCCCC	27.56	28176443
316	Phosphorylation	AQGNRQESTVSFNPY CCCCCCCCCEEECCC	26.27	26356563
317	Phosphorylation	QGNRQESTVSFNPYE CCCCCCCCEEECCCC	21.29	25394399
319	Phosphorylation	NRQESTVSFNPYEPE CCCCCCEEECCCCCH	21.28	22115753
323	Phosphorylation	STVSFNPYEPELAPW CCEEECCCCCHHHHC	45.26	27273156
334	Ubiquitination	LAPWAADKGPQREAL HHHCCCCCCCCCCCC	68.70	-
345	Phosphorylation	REALPMDTEVYESPY CCCCCCCCCEECCCC	22.54	25106551
348	Phosphorylation	LPMDTEVYESPYADP CCCCCCEECCCCCCH	12.40	22322096
350	Phosphorylation	MDTEVYESPYADPEE CCCCEECCCCCCHHH	12.91	27155012
352	Phosphorylation	TEVYESPYADPEEIR CCEECCCCCCHHHHC	32.68	21482705
364	Phosphorylation	EIRPKEVYLDRKLLT HHCCCEEEECCEEEE	12.18	21469132
379	Phosphorylation	LEDKELGSGNFGTVK CCHHCCCCCCCCCCC	43.09	21469132
384	Phosphorylation	LGSGNFGTVKKGYYQ CCCCCCCCCCHHHHH	25.64	21469132
389	Phosphorylation	FGTVKKGYYQMKKVV CCCCCHHHHHHHHHH	10.21	27155012
394	Acetylation	KGYYQMKKVVKTVAV HHHHHHHHHHHHHHH	47.09	30592747
402	Acetylation	VVKTVAVKILKNEAN HHHHHHHHHHHCCCC	32.36	30592753
431	Phosphorylation	MQQLDNPYIVRMIGI HHHCCCCHHHHHEEE	20.50	28064214
484	Phosphorylation	QVSMGMKYLEESNFV HHHHHHHHHHHCCCC	15.51	21469132
494 (in isoform 2)	Ubiquitination	-	26.28	21890473
504	Phosphorylation	ARNVLLVTQHYAKIS HHHHEEEEEEEEHHH	15.03	-
507	Phosphorylation	VLLVTQHYAKISDFG HEEEEEEEEHHHHCC	10.36	21469132
509	Ubiquitination	LVTQHYAKISDFGLS EEEEEEEHHHHCCHH	35.26	-
517 (in isoform 1)	Ubiquitination	-	57.38	21890473
517	Ubiquitination	ISDFGLSKALRADEN HHHCCHHHHHHCCCC	57.38	21890473
525	Phosphorylation	ALRADENYYKAQTHG HHHCCCCCHHCCCCC	12.33	22322096
526	Phosphorylation	LRADENYYKAQTHGK HHCCCCCHHCCCCCC	16.07	22322096
527	Ubiquitination	RADENYYKAQTHGKW HCCCCCHHCCCCCCC	24.53	-
530	Phosphorylation	ENYYKAQTHGKWPVK CCCHHCCCCCCCCCE	37.14	21469132
539	Phosphorylation	GKWPVKWYAPECINY CCCCCEEECHHHHCE	13.42	-
546	Phosphorylation	YAPECINYYKFSSKS ECHHHHCEEEECCHH	6.52	27259358
568	Phosphorylation	LMWEAFSYGQKPYRG HHHHHHHCCCCCCCC	19.68	22817900
571	Acetylation	EAFSYGQKPYRGMKG HHHHCCCCCCCCCCH	39.39	19814853
579	Phosphorylation	PYRGMKGSEVTAMLE CCCCCCHHHHHHHHH	24.31	21469132
582	Phosphorylation	GMKGSEVTAMLEKGE CCCHHHHHHHHHCCC	11.42	21469132
587	Ubiquitination	EVTAMLEKGERMGCP HHHHHHHCCCCCCCC	63.21	-
629	Phosphorylation	VELRLRNYYYDVVN- EEEEEHHCEEECCC-	9.29	30108239
630	Phosphorylation	ELRLRNYYYDVVN-- EEEEHHCEEECCC--	9.20	30108239
631	Phosphorylation	LRLRNYYYDVVN--- EEEHHCEEECCC---	7.60	30108239

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
178	S	Phosphorylation	Kinase	PRKAA1	Q13131	GPS
291	S	Phosphorylation	Kinase	PKC-FAMILY	-	GPS
295	S	Phosphorylation	Kinase	CHEK1	O14757	GPS
323	Y	Phosphorylation	Kinase	LYN	P07948	Uniprot
348	Y	Phosphorylation	Kinase	SYK	P43405	PSP
348	Y	Phosphorylation	Kinase	LYN	P07948	PSP
348	Y	Phosphorylation	Kinase	SYK	Q15046	PhosphoELM
352	Y	Phosphorylation	Kinase	SYK	P43405	PSP
352	Y	Phosphorylation	Kinase	LYN	P07948	PSP
352	Y	Phosphorylation	Kinase	SYK	Q15046	PhosphoELM
525	Y	Phosphorylation	Kinase	SYK	P43405	PSP
525	Y	Phosphorylation	Kinase	LYN	P07948	PSP
525	Y	Phosphorylation	Kinase	SYK	Q15046	PhosphoELM
526	Y	Phosphorylation	Kinase	SYK	P43405	PSP
526	Y	Phosphorylation	Kinase	LYN	P07948	PSP
526	Y	Phosphorylation	Kinase	SYK	Q15046	PhosphoELM
-	K	Ubiquitination	E3 ubiquitin ligase	CBL	P22681	PMID:11742985
-	K	Ubiquitination	E3 ubiquitin ligase	CBLB	Q13191	PMID:12771181
-	K	Ubiquitination	E3 ubiquitin ligase	NEDD4	P46934	PMID:11046148

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
297	S	Phosphorylation		21469132
Phosphorylation on Ser-297 is very common, it peaks 5 minutes after BCR stimulation, and creates a binding site for YWHAG.

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 KSYK_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
FAK2_HUMAN	PTK2B	physical	10747947
3BP2_HUMAN	SH3BP2	physical	9846481
LYN_HUMAN	LYN	physical	7831290
LAT_HUMAN	LAT	physical	11368773
VAV_HUMAN	VAV1	physical	8986718
KS6B1_HUMAN	RPS6KB1	physical	16640565
KS6B2_HUMAN	RPS6KB2	physical	16640565
KSYK_HUMAN	SYK	physical	9698567
KPCD1_HUMAN	PRKD1	physical	8885868
FCERG_HUMAN	FCER1G	physical	8071371
FCERB_HUMAN	MS4A2	physical	8071371
PHAG1_HUMAN	PAG1	physical	10790433
CD72_HUMAN	CD72	physical	9590210
ITB2_HUMAN	ITGB2	physical	10961871
SRC8_HUMAN	CTTN	physical	8636079
VAV_HUMAN	VAV1	physical	11331248
CBL_HUMAN	CBL	physical	12435267
FGR_HUMAN	FGR	physical	11672534
PAXI_HUMAN	PXN	physical	9590268
TRAF6_HUMAN	TRAF6	physical	11418661
TBA1A_HUMAN	TUBA1A	physical	10862713
CD3E_HUMAN	CD3E	physical	7761456
PTN6_HUMAN	PTPN6	physical	10072516
FCG2A_HUMAN	FCGR2A	physical	11141335
HDAC1_HUMAN	HDAC1	physical	16288017
HDAC3_HUMAN	HDAC3	physical	16288017
HDAC6_HUMAN	HDAC6	physical	16288017
HDAC9_HUMAN	HDAC9	physical	16288017
HDAC2_HUMAN	HDAC2	physical	16288017
HDAC4_HUMAN	HDAC4	physical	16288017
SP1_HUMAN	SP1	physical	16288017
TBG1_HUMAN	TUBG1	physical	16322234
UBP25_HUMAN	USP25	physical	19909739
SHIP1_HUMAN	INPP5D	physical	22267732
UBS3B_HUMAN	UBASH3B	physical	22267732
LCP2_HUMAN	LCP2	physical	22267732
SC23B_HUMAN	SEC23B	physical	22267732
NCK1_HUMAN	NCK1	physical	22267732
GRAP2_HUMAN	GRAP2	physical	22267732
GRB2_HUMAN	GRB2	physical	22267732
LCK_HUMAN	LCK	physical	15536084
P85B_HUMAN	PIK3R2	physical	15536084
FGR_HUMAN	FGR	physical	15536084
P85A_HUMAN	PIK3R1	physical	15536084
RS10_HUMAN	RPS10	physical	15536084
TYOBP_HUMAN	TYROBP	physical	9830044
B3AT_HUMAN	SLC4A1	physical	10605028
P85A_HUMAN	PIK3R1	physical	16921024
TRAIP_HUMAN	TRAIP	physical	19151749
CBL_HUMAN	CBL	physical	16289966
PK3CG_HUMAN	PIK3CG	physical	7721825
VAV2_HUMAN	VAV2	physical	11262396
VAV_HUMAN	VAV1	physical	11262396
CBL_HUMAN	CBL	physical	15556646
CBL_HUMAN	CBL	physical	7721825
TAU_HUMAN	MAPT	physical	18070606
KSYK_HUMAN	SYK	physical	18070606
A4_HUMAN	APP	physical	21832049
ERBB4_HUMAN	ERBB4	physical	16273093
KSYK_HUMAN	SYK	physical	16291755
SRC_HUMAN	SRC	physical	9389695
TRAF3_HUMAN	TRAF3	physical	23962979
TRAF6_HUMAN	TRAF6	physical	23962979
TBK1_HUMAN	TBK1	physical	23962979
M3K7_HUMAN	MAP3K7	physical	23962979
FCG3A_HUMAN	FCGR3A	physical	8189062
I17RA_HUMAN	IL17RA	physical	25202827
TRAF6_HUMAN	TRAF6	physical	25202827
CIKS_HUMAN	TRAF3IP2	physical	25202827
SH22A_HUMAN	SH2D2A	physical	25416956
UBP25_HUMAN	USP25	physical	25416956
FA46A_HUMAN	FAM46A	physical	25814554
HCLS1_HUMAN	HCLS1	physical	25241761
SRC8_HUMAN	CTTN	physical	25241761
FCGR1_HUMAN	FCGR1A	physical	25241761
HGS_HUMAN	HGS	physical	22706924
GRM1_HUMAN	GRM1	physical	15173175

Drug and Disease Associations

Kegg Disease
There are no disease associations of PTM sites.
OMIM Disease
There are no disease associations of PTM sites.
Kegg Drug
D09347	Fostamatinib (USAN)
D09348	Fostamatinib disodium (USAN)
DrugBank
There are no disease associations of PTM sites.

Regulatory Network of KSYK_HUMAN

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"Complex phosphorylation dynamics control the composition of the Sykinteractome in B cells."; Bohnenberger H., Oellerich T., Engelke M., Hsiao H.H., Urlaub H.,Wienands J.; Eur. J. Immunol. 41:1550-1562(2011). Cited for: PHOSPHORYLATION AT TYR-28; SER-44; TYR-47; TYR-131; SER-202; THR-256;SER-295; TYR-296; SER-297; SER-316; THR-317; SER-319; TYR-323;THR-345; TYR-348; SER-350; TYR-352; TYR-364; SER-379; THR-384;TYR-484; TYR-507; TYR-525; TYR-526; THR-530; SER-579; THR-582;TYR-629; TYR-630 AND TYR-631, INTERACTION WITH YWHAG, AND MUTAGENESISOF SER-297.	21469132 [Abstract]
"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 SER-295; TYR-296; SER-319;TYR-323 AND TYR-352, AND MASS SPECTROMETRY.	19369195 [Abstract]
"Phosphoproteome of resting human platelets."; Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,Schuetz C., Walter U., Gambaryan S., Sickmann A.; J. Proteome Res. 7:526-534(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-297, AND MASSSPECTROMETRY.	18088087 [Abstract]
"Quantitative phosphoproteomic analysis of T cell receptor signalingreveals system-wide modulation of protein-protein interactions."; Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,Rodionov V., Han D.K.; Sci. Signal. 2:RA46-RA46(2009). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-28, AND MASSSPECTROMETRY.	19690332 [Abstract]
"The kinase Syk as an adaptor controlling sustained calcium signallingand B-cell development."; Kulathu Y., Hobeika E., Turchinovich G., Reth M.; EMBO J. 27:1333-1344(2008). Cited for: INTERACTION WITH BLNK, ENZYME REGULATION, MUTAGENESIS OF TYR-630, ANDPHOSPHORYLATION AT TYR-630.	18369315 [Abstract]
"Multiple reaction monitoring for robust quantitative proteomicanalysis of cellular signaling networks."; Wolf-Yadlin A., Hautaniemi S., Lauffenburger D.A., White F.M.; Proc. Natl. Acad. Sci. U.S.A. 104:5860-5865(2007). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-323, AND MASSSPECTROMETRY.	17389395 [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-296; TYR-323; TYR-348;TYR-352 AND TYR-526, AND MASS SPECTROMETRY.	18083107 [Abstract]
"Profiling of tyrosine phosphorylation pathways in human cells usingmass spectrometry."; Salomon A.R., Ficarro S.B., Brill L.M., Brinker A., Phung Q.T.,Ericson C., Sauer K., Brock A., Horn D.M., Schultz P.G., Peters E.C.; Proc. Natl. Acad. Sci. U.S.A. 100:443-448(2003). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-348 AND TYR-352, ANDMASS SPECTROMETRY.	12522270 [Abstract]

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