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UniProtKB - Q9NRF2 (SH2B1_HUMAN)

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Protein

SH2B adapter protein 1

Gene

SH2B1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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).By similarity7 Publications

GO - Molecular functioni

Complete GO annotation...

GO - Biological processi

Complete GO annotation...

Enzyme and pathway databases

ReactomeiR-HSA-1170546. Prolactin receptor signaling.
R-HSA-2586552. Signaling by Leptin.
R-HSA-982772. Growth hormone receptor signaling.
R-HSA-983231. Factors involved in megakaryocyte development and platelet production.
SignaLinkiQ9NRF2.
SIGNORiQ9NRF2.

Names & Taxonomyi

Protein namesi
Recommended name:
SH2B adapter protein 1
Alternative name(s):
Pro-rich, PH and SH2 domain-containing signaling mediator
Short name:
PSM
SH2 domain-containing protein 1B
Gene namesi
Name:SH2B1
Synonyms:KIAA1299, SH2B
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

HGNCiHGNC:30417. SH2B1.

Subcellular locationi

  • Cytoplasm By similarity
  • Membrane Curated
  • Nucleus By similarity

    • Note: Shuttles between the nucleus and the cytoplasm.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi29F → R: Abolishes self-association and interaction with INSR and IGF1R. 1 Publication1
Mutagenesisi34A → D: Abolishes self-association and interaction with INSR and IGF1R. 1 Publication1
Mutagenesisi38A → D: Abolishes self-association and interaction with INSR and IGF1R. 1 Publication1
Mutagenesisi41F → A: Abolishes self-association and interaction with INSR and IGF1R. 1 Publication1
Mutagenesisi42A → D: Abolishes self-association and interaction with INSR and IGF1R. 1 Publication1
Mutagenesisi48Y → A: Abolishes self-association and interaction with INSR and IGF1R. 1 Publication1
Mutagenesisi68F → A: Abolishes self-association and interaction with INSR and IGF1R. 1 Publication1
Mutagenesisi72F → A: Abolishes self-association and interaction with INSR and IGF1R. 1 Publication1
Mutagenesisi555R → A: Abolishes self-association and interaction with INSR and IGF1R. 1 Publication1

Organism-specific databases

DisGeNETi25970.
MalaCardsiSH2B1.
OpenTargetsiENSG00000178188.
Orphaneti261222. Distal 16p11.2 microdeletion syndrome.
261197. Proximal 16p11.2 microdeletion syndrome.
329249. Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency.
PharmGKBiPA145148084.

Polymorphism and mutation databases

BioMutaiSH2B1.
DMDMi313104186.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00003235931 – 756SH2B adapter protein 1Add BLAST756

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei88PhosphoserineBy similarity1
Modified residuei96PhosphoserineCombined sources1
Modified residuei270Omega-N-methylarginineCombined sources1
Modified residuei417PhosphoserineBy similarity1
Modified residuei420PhosphoserineBy similarity1
Modified residuei439Phosphotyrosine; by JAK1, JAK2 and PDGFRBy similarity1
Modified residuei494Phosphotyrosine; by JAK1, JAK2By similarity1

Post-translational modificationi

Phosphorylated on tyrosine residues in response to receptor kinase stimulation. Phosphorylated by RET.3 Publications

Keywords - PTMi

Methylation, Phosphoprotein

Proteomic databases

EPDiQ9NRF2.
MaxQBiQ9NRF2.
PaxDbiQ9NRF2.
PeptideAtlasiQ9NRF2.
PRIDEiQ9NRF2.

PTM databases

iPTMnetiQ9NRF2.
PhosphoSitePlusiQ9NRF2.

Expressioni

Tissue specificityi

Widely expressed with highest levels in skeletal muscle and ovary.1 Publication

Gene expression databases

BgeeiENSG00000178188.
CleanExiHS_SH2B1.
ExpressionAtlasiQ9NRF2. baseline and differential.
GenevisibleiQ9NRF2. HS.

Organism-specific databases

HPAiHPA076175.

Interactioni

Subunit structurei

Self-associates. Homopentamer (By similarity). Forms a heteromultimeric complex with SH2B2 (By similarity). Interacts with SH2B2. Isoform 1 interacts via its SH2 domain with JAK2. Isoform 2 interacts via its SH2 domain and its N-terminus with JAK2; the SH2 domain is required for the major interaction with JAK2 phosphorylated on tyrosine residues; the N-terminus provides a low-affinity binding to JAK2 independent of JAK2 phosphorylation. Isoform 3 interacts via its SH2 domain with JAK2. Isoform 1 interacts via its SH2 domain with INSR; the interaction requires receptor activation. Isoform 3 interacts via its SH2 domain with INSR; the interaction requires receptor activation and requires INSR phosphorylation at 'Tyr-1185'. Isoform 1 interacts with IGF1R; the interaction requires receptor activation. Isoform 2 interacts with PRKAR1A/RET (PTC2) fusion protein; the interaction requires RET 'Tyr-905' and Tyr-981'. Isoform 2 interacts via its SH2 domain with FGFR3; the interaction requires FGFR3 'Tyr-724' and 'Tyr-760'. Isoform 2 interacts with RET; the interaction requires RET kinase activity and RET 'Tyr-981'. Isoform 2 interacts with RAC1. Isoform 2 interacts with PDGFRA and/or PDGFRB; the interaction requires receptor activation. Interacts with ISR1 and ISR2. Isoform 3 is probably part of a complex consisting of INSR, ISR1 and SH2B1. Probably part of a ternary complex consisting of SH2B1, JAK2 and ISR1 or ISR2. May interact with FCER1G (By similarity). Interacts (via SH2 domain) with NTRK1 (phosphorylated) (By similarity).By similarity

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi117455. 18 interactors.
IntActiQ9NRF2. 15 interactors.
MINTiMINT-1494470.
STRINGi9606.ENSP00000321221.

Structurei

3D structure databases

ProteinModelPortaliQ9NRF2.
SMRiQ9NRF2.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini267 – 376PHAdd BLAST110
Domaini527 – 625SH2PROSITE-ProRule annotationAdd BLAST99

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 555Interaction with JAK2 (low-affinity binding; independent of JAK2 phosphorylation)By similarityAdd BLAST555
Regioni24 – 85Required for self-associationAdd BLAST62
Regioni85 – 196Interaction with RAC1By similarityAdd BLAST112
Regioni100 – 243Required for NGF signalingBy similarityAdd BLAST144
Regioni224 – 233Required for nuclear localizationBy similarity10

Sequence similaritiesi

Belongs to the SH2B adapter family.Curated

Keywords - Domaini

SH2 domain

Phylogenomic databases

eggNOGiENOG410IMWK. Eukaryota.
ENOG41102PH. LUCA.
GeneTreeiENSGT00530000063355.
HOVERGENiHBG006707.
InParanoidiQ9NRF2.
KOiK12459.
OMAiGDRWTHR.
OrthoDBiEOG091G04RI.
PhylomeDBiQ9NRF2.
TreeFamiTF323184.

Family and domain databases

CDDicd10346. SH2_SH2B_family. 1 hit.
Gene3Di2.30.29.30. 1 hit.
3.30.505.10. 1 hit.
InterProiView protein in InterPro
IPR011993. PH_dom-like.
IPR001849. PH_domain.
IPR015012. Phe_ZIP.
IPR000980. SH2.
IPR030523. SH2B.
IPR030521. SH2B1.
IPR035057. SH2B1_SH2.
PANTHERiPTHR10872. PTHR10872. 1 hit.
PTHR10872:SF8. PTHR10872:SF8. 1 hit.
PfamiView protein in Pfam
PF00169. PH. 1 hit.
PF08916. Phe_ZIP. 1 hit.
PF00017. SH2. 1 hit.
PRINTSiPR00401. SH2DOMAIN.
SMARTiView protein in SMART
SM00233. PH. 1 hit.
SM00252. SH2. 1 hit.
SUPFAMiSSF109805. SSF109805. 1 hit.
SSF50729. SSF50729. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEiView protein in PROSITE
PS50001. SH2. 1 hit.

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9NRF2-1) [UniParc]FASTAAdd to basket
Also known as: Alpha

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MNGAPSPEDG ASPSSPPLPP PPPPSWREFC ESHARAAALD FARRFRLYLA 
        60         70         80         90        100
SHPQYAGPGA EAAFSRRFAE LFLQHFEAEV ARASGSLSPP ILAPLSPGAE 
       110        120        130        140        150
ISPHDLSLES CRVGGPLAVL GPSRSSEDLA GPLPSSVSSS STTSSKPKLK 
       160        170        180        190        200
KRFSLRSVGR SVRGSVRGIL QWRGTVDPPS SAGPLETSSG PPVLGGNSNS 
       210        220        230        240        250
NSSGGAGTVG RGLVSDGTSP GERWTHRFER LRLSRGGGAL KDGAGMVQRE 
       260        270        280        290        300
ELLSFMGAEE AAPDPAGVGR GGGVAGPPSG GGGQPQWQKC RLLLRSEGEG 
       310        320        330        340        350
GGGSRLEFFV PPKASRPRLS IPCSSITDVR TTTALEMPDR ENTFVVKVEG 
       360        370        380        390        400
PSEYIMETVD AQHVKAWVSD IQECLSPGPC PATSPRPMTL PLAPGTSFLT 
       410        420        430        440        450
RENTDSLELS CLNHSESLPS QDLLLGPSES NDRLSQGAYG GLSDRPSASI 
       460        470        480        490        500
SPSSASIAAS HFDSMELLPP ELPPRIPIEE GPPTGTVHPL SAPYPPLDTP 
       510        520        530        540        550
ETATGSFLFQ GEPEGGEGDQ PLSGYPWFHG MLSRLKAAQL VLTGGTGSHG 
       560        570        580        590        600
VFLVRQSETR RGEYVLTFNF QGKAKHLRLS LNEEGQCRVQ HLWFQSIFDM 
       610        620        630        640        650
LEHFRVHPIP LESGGSSDVV LVSYVPSSQR QQEPTTSHDP PQPPEPPSWT 
       660        670        680        690        700
DPPQPGAEEA SRAPEVAAAA AAAAKERQEK EKAGGGGVPE ELVPVVELVP 
       710        720        730        740        750
VVELEEAIAP GSEAQGAGSG GDAGVPPMVQ LQQSPLGGDG EEGGHPRAIN 

NQYSFV
Length:756
Mass (Da):79,366
Last modified:November 30, 2010 - v3
Checksum:iCF680B57114CB1D3
GO
Isoform 2 (identifier: Q9NRF2-2) [UniParc]FASTAAdd to basket
Also known as: Beta

The sequence of this isoform differs from the canonical sequence as follows:
     633-756: EPTTSHDPPQ...RAINNQYSFV → GREQAGSHAG...ASDCVTDHLP

Show »
Length:671
Mass (Da):70,781
Checksum:i3EAD9A95F370FD94
GO
Isoform 3 (identifier: Q9NRF2-3) [UniParc]FASTAAdd to basket
Also known as: Gamma

The sequence of this isoform differs from the canonical sequence as follows:
     633-756: EPTTSHDPPQ...RAINNQYSFV → GEQSRSAGEE...PSCPSERVTV

Show »
Length:683
Mass (Da):72,188
Checksum:i353155178527B5A7
GO

Sequence cautioni

The sequence AAH10704 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAA92537 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence BAB55148 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti197N → D in BAF83021 (PubMed:14702039).Curated1
Sequence conflicti519D → G in BAF83021 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_039550484T → A2 PublicationsCorresponds to variant dbSNP:rs7498665Ensembl.1
Natural variantiVAR_039551541V → A1 PublicationCorresponds to variant dbSNP:rs17850682Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_032027633 – 756EPTTS…QYSFV → GREQAGSHAGVCEGDGCHPD ASCTLMPFGASDCVTDHLP in isoform 2. 5 PublicationsAdd BLAST124
Alternative sequenceiVSP_032028633 – 756EPTTS…QYSFV → GEQSRSAGEEVPVHPRSEAG SRLGAMRGCAREMDATPMPP APSCPSERVTV in isoform 3. 2 PublicationsAdd BLAST124

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF227967 mRNA. Translation: AAF73912.1.
AF227968 mRNA. Translation: AAF73913.1.
AF227969 mRNA. Translation: AAF73914.1.
AB037720 mRNA. Translation: BAA92537.1. Different initiation.
AK027488 mRNA. Translation: BAB55148.1. Different initiation.
AK290332 mRNA. Translation: BAF83021.1.
AL049924 mRNA. Translation: CAB43208.1.
AL713760 mRNA. Translation: CAD28530.1.
AC133550 Genomic DNA. No translation available.
BC010704 mRNA. Translation: AAH10704.1. Different initiation.
CCDSiCCDS32424.1. [Q9NRF2-2]
CCDS53996.1. [Q9NRF2-1]
CCDS53997.1. [Q9NRF2-3]
PIRiT08662.
RefSeqiNP_001139267.1. NM_001145795.1. [Q9NRF2-1]
NP_001139268.1. NM_001145796.1. [Q9NRF2-2]
NP_001139269.1. NM_001145797.1. [Q9NRF2-3]
NP_001139284.1. NM_001145812.1. [Q9NRF2-2]
NP_001295222.1. NM_001308293.1. [Q9NRF2-1]
NP_001295223.1. NM_001308294.1.
NP_056318.2. NM_015503.2. [Q9NRF2-2]
XP_016878603.1. XM_017023114.1. [Q9NRF2-1]
XP_016878604.1. XM_017023115.1. [Q9NRF2-1]
XP_016878605.1. XM_017023116.1. [Q9NRF2-1]
UniGeneiHs.15744.

Genome annotation databases

EnsembliENST00000322610; ENSP00000321221; ENSG00000178188. [Q9NRF2-1]
ENST00000337120; ENSP00000337163; ENSG00000178188. [Q9NRF2-2]
ENST00000359285; ENSP00000352232; ENSG00000178188. [Q9NRF2-3]
ENST00000395532; ENSP00000378903; ENSG00000178188. [Q9NRF2-2]
ENST00000618521; ENSP00000481709; ENSG00000178188. [Q9NRF2-1]
GeneIDi25970.
KEGGihsa:25970.
UCSCiuc002dri.4. human. [Q9NRF2-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiSH2B1_HUMAN
AccessioniPrimary (citable) accession number: Q9NRF2
Secondary accession number(s): A8K2R7
, Q96FK3, Q96SX3, Q9NRF1, Q9NRF3, Q9P2P7, Q9Y3Y3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 18, 2008
Last sequence update: November 30, 2010
Last modified: June 7, 2017
This is version 133 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 16
    Human chromosome 16: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families