dbPTM

SH2B1_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	SH2B1_HUMAN
UniProt AC	Q9NRF2
Protein Name	SH2B adapter protein 1
Gene Name	SH2B1
Organism	Homo sapiens (Human).
Sequence Length	756
Subcellular Localization	Cytoplasm. Membrane . Nucleus. Shuttles between the nucleus and the cytoplasm..
Protein Description	Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases, including the receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1, which in turn is phosphorylated by JAK2 on tyrosine residues. These phosphotyrosines form potential binding sites for other signaling proteins. GH also promotes serine/threonine phosphorylation of SH2B1 and these phosphorylated residues may serve to recruit other proteins to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP) signaling, binds to and potentiates the activation of JAK2 by globally enhancing downstream pathways. In response to leptin, binds simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-kinase pathway. Acts as positive regulator of NGF-mediated activation of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase activity of the cytokine receptor-associated tyrosine kinase JAK2 and of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2, the mechanism seems to involve dimerization of both, SH2B1 and JAK2. Enhances RET phosphorylation and kinase activity. Isoforms seem to be differentially involved in IGF-I and PDGF-induced mitogenesis (By similarity)..
Protein Sequence	MNGAPSPEDGASPSSPPLPPPPPPSWREFCESHARAAALDFARRFRLYLASHPQYAGPGAEAAFSRRFAELFLQHFEAEVARASGSLSPPILAPLSPGAEISPHDLSLESCRVGGPLAVLGPSRSSEDLAGPLPSSVSSSSTTSSKPKLKKRFSLRSVGRSVRGSVRGILQWRGTVDPPSSAGPLETSSGPPVLGGNSNSNSSGGAGTVGRGLVSDGTSPGERWTHRFERLRLSRGGGALKDGAGMVQREELLSFMGAEEAAPDPAGVGRGGGVAGPPSGGGGQPQWQKCRLLLRSEGEGGGGSRLEFFVPPKASRPRLSIPCSSITDVRTTTALEMPDRENTFVVKVEGPSEYIMETVDAQHVKAWVSDIQECLSPGPCPATSPRPMTLPLAPGTSFLTRENTDSLELSCLNHSESLPSQDLLLGPSESNDRLSQGAYGGLSDRPSASISPSSASIAASHFDSMELLPPELPPRIPIEEGPPTGTVHPLSAPYPPLDTPETATGSFLFQGEPEGGEGDQPLSGYPWFHGMLSRLKAAQLVLTGGTGSHGVFLVRQSETRRGEYVLTFNFQGKAKHLRLSLNEEGQCRVQHLWFQSIFDMLEHFRVHPIPLESGGSSDVVLVSYVPSSQRQQEPTTSHDPPQPPEPPSWTDPPQPGAEEASRAPEVAAAAAAAAKERQEKEKAGGGGVPEELVPVVELVPVVELEEAIAPGSEAQGAGSGGDAGVPPMVQLQQSPLGGDGEEGGHPRAINNQYSFV

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
25	Phosphorylation	LPPPPPPSWREFCES CCCCCCCCHHHHHHH	44.53	26091039
48	Phosphorylation	FARRFRLYLASHPQY HHHHHHHHHHHCCCC	8.93	-
51	Phosphorylation	RFRLYLASHPQYAGP HHHHHHHHCCCCCCC	32.86	19060867
55	Phosphorylation	YLASHPQYAGPGAEA HHHHCCCCCCCCHHH	20.27	21253578
65	Phosphorylation	PGAEAAFSRRFAELF CCHHHHHHHHHHHHH	20.16	-
84	Phosphorylation	EAEVARASGSLSPPI HHHHHHHCCCCCCCE	24.30	21712546
86	Phosphorylation	EVARASGSLSPPILA HHHHHCCCCCCCEEE	24.15	28102081
88	Phosphorylation	ARASGSLSPPILAPL HHHCCCCCCCEEECC	30.26	22617229
96	Phosphorylation	PPILAPLSPGAEISP CCEEECCCCCCCCCC	21.89	26055452
102	Phosphorylation	LSPGAEISPHDLSLE CCCCCCCCCCCCCCC	14.00	30206219
107	Phosphorylation	EISPHDLSLESCRVG CCCCCCCCCCCCCCC	35.83	28450419
110	Phosphorylation	PHDLSLESCRVGGPL CCCCCCCCCCCCCCE	16.71	28450419
123	Phosphorylation	PLAVLGPSRSSEDLA CEEEECCCCCCCCCC	42.89	23927012
125	Phosphorylation	AVLGPSRSSEDLAGP EEECCCCCCCCCCCC	42.28	23401153
126	Phosphorylation	VLGPSRSSEDLAGPL EECCCCCCCCCCCCC	33.74	30266825
135	Phosphorylation	DLAGPLPSSVSSSST CCCCCCCCCCCCCCC	51.56	23927012
136	Phosphorylation	LAGPLPSSVSSSSTT CCCCCCCCCCCCCCC	24.87	23927012
138	Phosphorylation	GPLPSSVSSSSTTSS CCCCCCCCCCCCCCC	26.84	23927012
139	Phosphorylation	PLPSSVSSSSTTSSK CCCCCCCCCCCCCCC	26.59	23927012
140	Phosphorylation	LPSSVSSSSTTSSKP CCCCCCCCCCCCCCC	24.97	23927012
141	Phosphorylation	PSSVSSSSTTSSKPK CCCCCCCCCCCCCCC	37.34	23927012
142	Phosphorylation	SSVSSSSTTSSKPKL CCCCCCCCCCCCCCH	32.42	23927012
143	Phosphorylation	SVSSSSTTSSKPKLK CCCCCCCCCCCCCHH	32.71	23927012
144	Phosphorylation	VSSSSTTSSKPKLKK CCCCCCCCCCCCHHH	36.13	23927012
145	Phosphorylation	SSSSTTSSKPKLKKR CCCCCCCCCCCHHHC	51.38	23403867
154	Phosphorylation	PKLKKRFSLRSVGRS CCHHHCEEEHHHCCC	27.23	30576142
157	Phosphorylation	KKRFSLRSVGRSVRG HHCEEEHHHCCCHHH	33.93	30576142
161	Phosphorylation	SLRSVGRSVRGSVRG EEHHHCCCHHHHHHH	15.38	21878491
165	Phosphorylation	VGRSVRGSVRGILQW HCCCHHHHHHHHEEE	9.70	21878491
189	Phosphorylation	AGPLETSSGPPVLGG CCCCCCCCCCCCCCC	63.84	28555341
211	Methylation	GGAGTVGRGLVSDGT CCCCCCCCCCCCCCC	30.82	115916833
215	Phosphorylation	TVGRGLVSDGTSPGE CCCCCCCCCCCCCCC	35.05	27251275
218	Phosphorylation	RGLVSDGTSPGERWT CCCCCCCCCCCCHHC	36.42	29255136
219	Phosphorylation	GLVSDGTSPGERWTH CCCCCCCCCCCHHCH	36.12	29255136
235	Methylation	FERLRLSRGGGALKD HHHHHCCCCCCCCCC	52.98	58859443
270	Methylation	PDPAGVGRGGGVAGP CCCCCCCCCCCCCCC	37.87	24129315
279	Phosphorylation	GGVAGPPSGGGGQPQ CCCCCCCCCCCCCCH	53.88	28555341
289	Ubiquitination	GGQPQWQKCRLLLRS CCCCHHHCCEEEEEC	20.54	-
296	Phosphorylation	KCRLLLRSEGEGGGG CCEEEEECCCCCCCC	50.34	28555341
320	Phosphorylation	KASRPRLSIPCSSIT CCCCCCEECCCCCCC	26.26	24275569
324	Phosphorylation	PRLSIPCSSITDVRT CCEECCCCCCCCCEE	21.30	28348404
325	Phosphorylation	RLSIPCSSITDVRTT CEECCCCCCCCCEEC	35.90	28857561
327	Phosphorylation	SIPCSSITDVRTTTA ECCCCCCCCCEECEE	30.32	28348404
352	Phosphorylation	VVKVEGPSEYIMETV EEEEECCCCCEEEEC	54.62	29116813
354	Phosphorylation	KVEGPSEYIMETVDA EEECCCCCEEEECCH	15.20	27642862
369	Phosphorylation	QHVKAWVSDIQECLS HHHHHHHHHHHHHCC	20.49	28102081
376	Phosphorylation	SDIQECLSPGPCPAT HHHHHHCCCCCCCCC	39.20	29978859
383	Phosphorylation	SPGPCPATSPRPMTL CCCCCCCCCCCCCCC	25.14	29978859
384	Phosphorylation	PGPCPATSPRPMTLP CCCCCCCCCCCCCCC	22.48	29978859
389	Phosphorylation	ATSPRPMTLPLAPGT CCCCCCCCCCCCCCC	28.10	26074081
396	Phosphorylation	TLPLAPGTSFLTREN CCCCCCCCCEECCCC	18.42	26074081
397	Phosphorylation	LPLAPGTSFLTRENT CCCCCCCCEECCCCC	24.95	26074081
400	Phosphorylation	APGTSFLTRENTDSL CCCCCEECCCCCCCE	33.65	26074081
404	Phosphorylation	SFLTRENTDSLELSC CEECCCCCCCEEEEC	23.39	28857561
406	Phosphorylation	LTRENTDSLELSCLN ECCCCCCCEEEECCC	23.00	28857561
410	Phosphorylation	NTDSLELSCLNHSES CCCCEEEECCCCCCC	13.74	28857561
415	Phosphorylation	ELSCLNHSESLPSQD EEECCCCCCCCCCCC	28.01	28857561
417	Phosphorylation	SCLNHSESLPSQDLL ECCCCCCCCCCCCEE	48.90	28857561
420	Phosphorylation	NHSESLPSQDLLLGP CCCCCCCCCCEECCC	41.44	-
439	Phosphorylation	DRLSQGAYGGLSDRP CCCCCCCCCCCCCCC	20.67	25884760
494	Phosphorylation	VHPLSAPYPPLDTPE CCCCCCCCCCCCCCC	19.73	12551917
580	Phosphorylation	KAKHLRLSLNEEGQC CEEEEEEECCCCCCH	23.79	26657352
624	Phosphorylation	SDVVLVSYVPSSQRQ CCEEEEEECCCCCCC	14.65	19534553
649 (in isoform 3)	Phosphorylation	-	15.59	22210691
678 (in isoform 3)	Phosphorylation	-	68.17	22210691
753	Phosphorylation	PRAINNQYSFV---- CCCCCCCCCCC----	13.24	27642862

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
96	S	Phosphorylation	Kinase	MAPK1	P28482	GPS
96	S	Phosphorylation	Kinase	MAPK3	P27361	GPS
161	S	Phosphorylation	Kinase	PRKCA	P17252	GPS
165	S	Phosphorylation	Kinase	PRKCA	P17252	GPS
439	Y	Phosphorylation	Kinase	JAK1	P23458	Uniprot
439	Y	Phosphorylation	Kinase	JAK2	O60674	Uniprot
439	Y	Phosphorylation	Kinase	PDGFR-FAMILY	-	GPS
439	Y	Phosphorylation	Kinase	PDGFR	-	Uniprot
494	Y	Phosphorylation	Kinase	JAK1	P23458	Uniprot
494	Y	Phosphorylation	Kinase	JAK2	O60674	Uniprot
753	Y	Phosphorylation	Kinase	TRKA	P04629	PSP

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
Oops, there are no descriptions of PTM sites of SH2B1_HUMAN !!

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
145	Phosphorylation	148 (3)	T ⇒ A;S	rs7498665	Waist circumference Body mass index	25673412 19079261 23563607 19079260
154	Phosphorylation	148 (6)	T ⇒ A;S	rs7498665	Waist circumference Body mass index	25673412 19079261 23563607 19079260
157	Phosphorylation	148 (9)	T ⇒ A;S	rs7498665	Waist circumference Body mass index	25673412 19079261 23563607 19079260

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
FGFR3_HUMAN	FGFR3	physical	11827956
NTRK1_HUMAN	NTRK1	physical	9856458
GRB2_HUMAN	GRB2	physical	9856458
JAK2_HUMAN	JAK2	physical	9343427
JAK2_HUMAN	JAK2	physical	12370803
INSR_HUMAN	INSR	physical	10594240
JAK2_HUMAN	JAK2	physical	17565041
BRCA1_HUMAN	BRCA1	physical	17565041
SH2B1_HUMAN	SH2B1	physical	15767667
SH2B2_HUMAN	SH2B2	physical	15767667
JAK2_HUMAN	JAK2	physical	15767667
INSR_HUMAN	INSR	physical	15767667
IGF1R_HUMAN	IGF1R	physical	15767667
CSAD_HUMAN	CSAD	physical	25814554

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
There are no disease associations of PTM sites.
DrugBank
There are no disease associations of PTM sites.

Regulatory Network of SH2B1_HUMAN

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"A quantitative atlas of mitotic phosphorylation."; Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,Elledge S.J., Gygi S.P.; Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-88 AND SER-96, AND MASSSPECTROMETRY.	18669648 [Abstract]
"Combining protein-based IMAC, peptide-based IMAC, and MudPIT forefficient phosphoproteomic analysis."; Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,Yates J.R. III; J. Proteome Res. 7:1346-1351(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-88 AND SER-96, AND MASSSPECTROMETRY.	18220336 [Abstract]
"An extensive survey of tyrosine phosphorylation revealing new sitesin human mammary epithelial cells."; Heibeck T.H., Ding S.-J., Opresko L.K., Zhao R., Schepmoes A.A.,Yang F., Tolmachev A.V., Monroe M.E., Camp D.G. II, Smith R.D.,Wiley H.S., Qian W.-J.; J. Proteome Res. 8:3852-3861(2009). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-624, AND MASSSPECTROMETRY.	19534553 [Abstract]