SH2B2_RAT
ID SH2B2_RAT Reviewed; 621 AA.
AC Q9Z200;
DT 29-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=SH2B adapter protein 2;
DE AltName: Full=Adapter protein with pleckstrin homology and Src homology 2 domains;
DE AltName: Full=SH2 and PH domain-containing adapter protein APS;
GN Name=Sh2b2; Synonyms=Aps;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION IN NGF SIGNALING, INTERACTION WITH
RP GRB2; NTRK1; NTRK2 AND NTRK3, PHOSPHORYLATION, AND TISSUE SPECIFICITY.
RC TISSUE=Fetal spinal cord, and Hippocampus;
RX PubMed=9856458; DOI=10.1016/s0896-6273(00)80620-0;
RA Qian X., Riccio A., Zhang Y., Ginty D.D.;
RT "Identification and characterization of novel substrates of Trk receptors
RT in developing neurons.";
RL Neuron 21:1017-1029(1998).
RN [2]
RP FUNCTION, INTERACTION WITH INSR AND CBL, AND PHOSPHORYLATION.
RX PubMed=10854852; DOI=10.1016/s0014-5793(00)01621-5;
RA Ahmed Z., Smith B.J., Pillay T.S.;
RT "The APS adapter protein couples the insulin receptor to the
RT phosphorylation of c-Cbl and facilitates ligand-stimulated ubiquitination
RT of the insulin receptor.";
RL FEBS Lett. 475:31-34(2000).
RN [3]
RP FUNCTION, INTERACTION WITH CBL AND CAP, AND PHOSPHORYLATION AT TYR-618.
RX PubMed=11997497; DOI=10.1128/mcb.22.11.3599-3609.2002;
RA Liu J., Kimura A., Baumann C.A., Saltiel A.R.;
RT "APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in
RT response to insulin in 3T3-L1 adipocytes.";
RL Mol. Cell. Biol. 22:3599-3609(2002).
RN [4]
RP FUNCTION, AND INTERACTION WITH INSR; CAP AND CBL.
RX PubMed=15031295; DOI=10.1074/jbc.m307740200;
RA Ahn M.-Y., Katsanakis K.D., Bheda F., Pillay T.S.;
RT "Primary and essential role of the adaptor protein APS for recruitment of
RT both c-Cbl and its associated protein CAP in insulin signaling.";
RL J. Biol. Chem. 279:21526-21532(2004).
RN [5]
RP INTERACTION WITH ASB6.
RX PubMed=15231829; DOI=10.1074/jbc.m406101200;
RA Wilcox A., Katsanakis K.D., Bheda F., Pillay T.S.;
RT "Asb6, an adipocyte-specific ankyrin and SOCS box protein, interacts with
RT APS to enable recruitment of elongins B and C to the insulin receptor
RT signaling complex.";
RL J. Biol. Chem. 279:38881-38888(2004).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 401-510 IN COMPLEX WITH
RP PHOSPHORYLATED INSR, MUTAGENESIS OF ARG-437; LYS-455 AND LYS-457, AND
RP HOMODIMERIZATION.
RX PubMed=14690593; DOI=10.1016/s1097-2765(03)00487-8;
RA Hu J., Liu J., Ghirlando R., Saltiel A.R., Hubbard S.R.;
RT "Structural basis for recruitment of the adaptor protein APS to the
RT activated insulin receptor.";
RL Mol. Cell 12:1379-1389(2003).
CC -!- FUNCTION: Adapter protein for several members of the tyrosine kinase
CC receptor family. Involved in multiple signaling pathways. Binds to EPOR
CC and suppresses EPO-induced STAT5 activation, possibly through a masking
CC effect on STAT5 docking sites in EPOR. Suppresses PDGF-induced
CC mitogenesis (By similarity). Involved in stimulation of glucose uptake
CC by insulin. Involved in coupling from immunoreceptor to Ras signaling.
CC Acts as a negative regulator of cytokine signaling in collaboration
CC with CBL. Induces cytoskeletal reorganization and neurite outgrowth in
CC cultured neurons. {ECO:0000250, ECO:0000269|PubMed:10854852,
CC ECO:0000269|PubMed:11997497, ECO:0000269|PubMed:15031295,
CC ECO:0000269|PubMed:9856458}.
CC -!- SUBUNIT: Homodimer. Interacts with KIT/c-KIT, SHC1, EPOR, PDGFR, VAV1
CC and VAV3. Interacts (via N-terminal region) with SHC1. Interacts (via
CC the phosphorylated C-terminus) with GRB2. Interacts (via its SH2
CC domain) with EPOR, INSR and KIT. Interacts with GRB2 after B-cell
CC antigen receptor stimulation. Interacts (via PH domain) with VAV3 (By
CC similarity). Interacts with NTRK1, NTRK2 and NTRK3 (phosphorylated);
CC after stimulation of the receptor by its extracellular ligand and
CC subsequent autophosphorylation of the receptor. Binds INSR, GRB2, ASB6
CC and CAP. Insulin stimulation leads to dissociation of CAP. Binds CBS
CC only when SH2B2/APS has become phosphorylated. INSR binding does not
CC depend on the phosphorylation of SH2B2/APS. {ECO:0000250,
CC ECO:0000269|PubMed:10854852, ECO:0000269|PubMed:11997497,
CC ECO:0000269|PubMed:14690593, ECO:0000269|PubMed:15031295,
CC ECO:0000269|PubMed:15231829, ECO:0000269|PubMed:9856458}.
CC -!- INTERACTION:
CC Q9Z200; Q9Z200: Sh2b2; NbExp=2; IntAct=EBI-8562298, EBI-8562298;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane. Note=Recruited to the
CC membrane by binding to an autophosphorylated receptor after receptor
CC stimulation by its extracellular ligand.
CC -!- TISSUE SPECIFICITY: Detected in embryonic brain, spinal cord and
CC cortical neurons. {ECO:0000269|PubMed:9856458}.
CC -!- PTM: Phosphorylated on a tyrosine residue by NTRK1, NTRK2, NTRK3 and
CC INSR after stimulation of the receptor by its extracellular ligand.
CC Tyrosine phosphorylated by JAK2, KIT and other kinases activated by B-
CC cell receptor in response to stimulation with cytokines, IL3, IL5,
CC PDGF, IGF1, IGF2, CSF2/GM-CSF and cross-linking of the B-cell receptor
CC complex (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the SH2B adapter family. {ECO:0000305}.
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DR EMBL; AF095576; AAC64408.1; -; mRNA.
DR RefSeq; NP_446121.1; NM_053669.1.
DR RefSeq; XP_008767335.1; XM_008769113.2.
DR RefSeq; XP_017453727.1; XM_017598238.1.
DR RefSeq; XP_017453728.1; XM_017598239.1.
DR PDB; 1RPY; X-ray; 2.30 A; A/B=401-510.
DR PDB; 1RQQ; X-ray; 2.60 A; C/D=401-510.
DR PDB; 1YVH; X-ray; 2.05 A; B=609-621.
DR PDBsum; 1RPY; -.
DR PDBsum; 1RQQ; -.
DR PDBsum; 1YVH; -.
DR AlphaFoldDB; Q9Z200; -.
DR BMRB; Q9Z200; -.
DR SMR; Q9Z200; -.
DR BioGRID; 250306; 1.
DR IntAct; Q9Z200; 2.
DR MINT; Q9Z200; -.
DR STRING; 10116.ENSRNOP00000001935; -.
DR iPTMnet; Q9Z200; -.
DR PhosphoSitePlus; Q9Z200; -.
DR PaxDb; Q9Z200; -.
DR Ensembl; ENSRNOT00000001935; ENSRNOP00000001935; ENSRNOG00000001425.
DR GeneID; 114203; -.
DR KEGG; rno:114203; -.
DR UCSC; RGD:69284; rat.
DR CTD; 10603; -.
DR RGD; 69284; Sh2b2.
DR eggNOG; ENOG502QT43; Eukaryota.
DR GeneTree; ENSGT00950000183191; -.
DR HOGENOM; CLU_014885_5_0_1; -.
DR InParanoid; Q9Z200; -.
DR OMA; KMEGERF; -.
DR OrthoDB; 556279at2759; -.
DR PhylomeDB; Q9Z200; -.
DR Reactome; R-RNO-1433559; Regulation of KIT signaling.
DR Reactome; R-RNO-983231; Factors involved in megakaryocyte development and platelet production.
DR EvolutionaryTrace; Q9Z200; -.
DR PRO; PR:Q9Z200; -.
DR Proteomes; UP000002494; Chromosome 12.
DR Bgee; ENSRNOG00000001425; Expressed in spleen and 18 other tissues.
DR Genevisible; Q9Z200; RN.
DR GO; GO:0005884; C:actin filament; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0001726; C:ruffle; ISO:RGD.
DR GO; GO:0001725; C:stress fiber; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0042169; F:SH2 domain binding; ISO:RGD.
DR GO; GO:0035591; F:signaling adaptor activity; ISO:RGD.
DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; ISO:RGD.
DR GO; GO:0030036; P:actin cytoskeleton organization; ISO:RGD.
DR GO; GO:0050851; P:antigen receptor-mediated signaling pathway; ISO:RGD.
DR GO; GO:0050853; P:B cell receptor signaling pathway; ISO:RGD.
DR GO; GO:0001922; P:B-1 B cell homeostasis; ISO:RGD.
DR GO; GO:0050873; P:brown fat cell differentiation; ISO:RGD.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISO:RGD.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISO:RGD.
DR GO; GO:0035556; P:intracellular signal transduction; ISO:RGD.
DR GO; GO:0007399; P:nervous system development; IMP:RGD.
DR GO; GO:0050776; P:regulation of immune response; ISO:RGD.
DR GO; GO:0019222; P:regulation of metabolic process; ISO:RGD.
DR GO; GO:0046578; P:regulation of Ras protein signal transduction; IDA:RGD.
DR CDD; cd10411; SH2_SH2B2; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR IDEAL; IID50237; -.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR015012; Phe_ZIP.
DR InterPro; IPR036290; Phe_ZIP_sf.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR030523; SH2B.
DR InterPro; IPR030520; SH2B2.
DR InterPro; IPR035058; SH2B2_SH2.
DR PANTHER; PTHR10872; PTHR10872; 1.
DR PANTHER; PTHR10872:SF4; PTHR10872:SF4; 1.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF08916; Phe_ZIP; 1.
DR Pfam; PF00017; SH2; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00252; SH2; 1.
DR SUPFAM; SSF109805; SSF109805; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Membrane; Phosphoprotein; Reference proteome;
KW SH2 domain.
FT CHAIN 1..621
FT /note="SH2B adapter protein 2"
FT /id="PRO_0000064649"
FT DOMAIN 186..299
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 409..507
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT REGION 144..165
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 507..528
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 548..609
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 548..572
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 47
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9JID9"
FT MOD_RES 130
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JID9"
FT MOD_RES 303
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JID9"
FT MOD_RES 597
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JID9"
FT MOD_RES 618
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:11997497"
FT MUTAGEN 437
FT /note="R->A: Abolishes interaction with phosphorylated
FT INSR."
FT /evidence="ECO:0000269|PubMed:14690593"
FT MUTAGEN 455
FT /note="K->A: Reduces interaction with phosphorylated INSR."
FT /evidence="ECO:0000269|PubMed:14690593"
FT MUTAGEN 457
FT /note="K->N: Abolishes interaction with phosphorylated
FT INSR."
FT /evidence="ECO:0000269|PubMed:14690593"
FT MUTAGEN 618
FT /note="Y->F: Abolishes phosphorylation in response to
FT insulin."
FT HELIX 404..406
FT /evidence="ECO:0007829|PDB:1RPY"
FT HELIX 416..424
FT /evidence="ECO:0007829|PDB:1RPY"
FT HELIX 427..430
FT /evidence="ECO:0007829|PDB:1RPY"
FT STRAND 434..438
FT /evidence="ECO:0007829|PDB:1RPY"
FT STRAND 440..442
FT /evidence="ECO:0007829|PDB:1RPY"
FT STRAND 446..452
FT /evidence="ECO:0007829|PDB:1RPY"
FT STRAND 455..460
FT /evidence="ECO:0007829|PDB:1RPY"
FT HELIX 469..486
FT /evidence="ECO:0007829|PDB:1RPY"
SQ SEQUENCE 621 AA; 66708 MW; 4E019DF3A73D5B4F CRC64;
MNGATPGSAA APAPVPDWRQ FCELHAQVAA VDFAHKFCRF LRDNPTYDTP DAGTSFSRHF
AANFLAVFSE EVRRVLGTAA DTMEPEPAVT SVTSALKTAT YGHSRSSEDV SAHVATKARV
RKGFSLRNMS LCVVDGVRDL WHRRASPEPE GGATPKTTEP VSEPRDKWTR RLRLARTLAA
KVELVDIQRE GALRFMVADD AASGPGGTAQ WQKCRLLLRR AVAGERFRLE FFVPPKASRP
KVSIPLSAII EVRTTMPLEM PEKDNTFVLK VENGAEYILE TIDSLQKHSW VADIQGCVDP
GDSEEDTGLS CARGGCLASR VTSCSCELLT EADMPRPPET MTAVGAVVTA PHGRARDTVG
ESLAHVPLET FLQTLESSGG VSESNNTGDE GAELDPDAEA ELELSDYPWF HGTLSRVKAA
QLVLAGGPRS HGLFVIRQSE TRPGECVLTF NFQGKAKHLR LSLNGHGQCH VQHLWFQSVF
DMLRHFHTHP IPLESGGSAD ITLRSYVRAQ GPPPDPGPAP NTAAPVPACW TEPAGQHYFS
SLATATCPPT SPSNGAGASS SSGSSSSATS VPPRPAEGPL SARSRSNSTE HLLEAASGAT
EEPADATLGR ARAVENQYSF Y
