Reviewed, UniProtKB/Swiss-Prot P35570 (IRS1_RAT)

Names and origin

Protein names

Recommended name:
    Insulin receptor substrate 1
      Short name=IRS-1
Alternative name(s):
    pp185

Gene names

Name:	Irs1
Synonyms:	Irs-1

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	1235 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit. Ref.3
Subunit structure	Interacts with SOCS7 By similarity. Interacts with the NPXY motif of tyrosine-phosphorylated IGF1R and INSR via the PTB domain. Binds to phosphatidylinositol 3-kinase p85 subunit via the phosphorylated YXXM motifs. Binds ROCK1.
Post-translational modification	Serine phosphorylation of IRS1 is a mechanism for insulin resistance. Ser-307 phosphorylation inhibits insulin action through disruption of IRS1 interaction with the insulin receptor, and Ser-789 phosphorylation is increased in the liver of insulin-resistant rats. Phosphorylation of Tyr-895 is required for GRB2-binding.
Sequence similarities	Contains 1 IRS-type PTB domain. Contains 1 PH domain.

Ontologies

Keywords
Domain	Repeat
Molecular function	Transducer
PTM	Phosphoprotein
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	insulin receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB insulin-like growth factor receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of insulin receptor signaling pathway Inferred from mutant phenotype. Source: UniProtKB positive regulation of insulin receptor signaling pathway Inferred from mutant phenotype. Source: UniProtKB positive regulation of phosphoinositide 3-kinase activity Ref.3 Inferred from direct assay. Source: UniProtKB protein heterooligomerization Inferred from direct assay. Source: RGD
Cellular component	cytosol Inferred from direct assay. Source: RGD insulin receptor complex Inferred from mutant phenotype. Source: UniProtKB microsome Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	SH2 domain binding Ref.4 Inferred from physical interaction. Source: UniProtKB insulin receptor binding Inferred from sequence or structural similarity. Source: UniProtKB insulin-like growth factor receptor activity Inferred from mutant phenotype. Source: RGD insulin-like growth factor receptor binding Inferred from sequence or structural similarity. Source: UniProtKB phosphoinositide 3-kinase binding Ref.3 Inferred from direct assay. Source: UniProtKB protein kinase C binding Inferred from physical interaction. Source: UniProtKB transmembrane receptor protein tyrosine kinase docking protein activity Inferred from mutant phenotype. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Phip	Q8VDD9	1	EBI-520230,EBI-1369766	From a different organism.
TP53BP2	Q13625-2	1	EBI-520230,EBI-287091	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1235	1235	Insulin receptor substrate 1		PRO_0000084238
Regions
	Domain	12 – 115	104	PH
	Domain	155 – 259	105	IRS-type PTB
	Region	895 – 897	3	GRB2-binding
	Motif	460 – 463	4	YXXM motif 1
	Motif	546 – 549	4	YXXM motif 2
	Motif	608 – 611	4	YXXM motif 3
	Motif	628 – 631	4	YXXM motif 4
	Motif	658 – 661	4	YXXM motif 5
	Motif	727 – 730	4	YXXM motif 6
	Motif	939 – 942	4	YXXM motif 7
	Motif	987 – 990	4	YXXM motif 8
	Motif	1010 – 1013	4	YXXM motif 9
	Compositional bias	872 – 881	10	Poly-Gln
	Compositional bias	1196 – 1200	5	Poly-Pro
Amino acid modifications
	Modified residue	3	1	Phosphoserine By similarity
	Modified residue	46	1	Phosphotyrosine By similarity
	Modified residue	99	1	Phosphoserine; by CK2 Ref.6
	Modified residue	307	1	Phosphoserine Ref.7
	Modified residue	324	1	Phosphoserine By similarity
	Modified residue	340	1	Phosphoserine By similarity
	Modified residue	460	1	Phosphotyrosine; by INSR Ref.5
	Modified residue	502	1	Phosphothreonine; by CK2 Ref.6
	Modified residue	526	1	Phosphoserine By similarity
	Modified residue	608	1	Phosphotyrosine; by INSR Ref.5
	Modified residue	628	1	Phosphotyrosine; by INSR
	Modified residue	632	1	Phosphoserine By similarity
	Modified residue	658	1	Phosphotyrosine By similarity
	Modified residue	789	1	Phosphoserine; by SNF1LK2 Ref.8
	Modified residue	895	1	Phosphotyrosine; by INSR Ref.5
	Modified residue	939	1	Phosphotyrosine; by INSR Ref.5
	Modified residue	987	1	Phosphotyrosine; by INSR Ref.5
	Modified residue	1100	1	Phosphoserine By similarity
	Modified residue	1138	1	Phosphoserine By similarity
	Modified residue	1172	1	Phosphotyrosine; by INSR Ref.5
	Modified residue	1216	1	Phosphoserine By similarity
	Modified residue	1222	1	Phosphotyrosine; by INSR Ref.5
Experimental info
	Sequence conflict	1098	1	H → L AA sequence Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P35570-1 [UniParc]. Last modified June 1, 1994. Version 1. Checksum: A274BC7540CA85C5	FASTA	1,235	131,178
	10 20 30 40 50 60 MASPPDTDGF SDVRKVGYLR KPKSMHKRFF VLRAASEAGG PARLEYYENE KKWRHKSSAP 70 80 90 100 110 120 KRSIPLESCF NINKRADSKN KHLVALYTRD EHFAIAADSE AEQDSWYQAL LQLHNRAKAH 130 140 150 160 170 180 HDGAGGGCGG SCSGSSGVGE AGEDLSYDTG PGPAFKEVWQ VILKPKGLGQ TKNLIGIYRL 190 200 210 220 230 240 CLTSKTISFV KLNSEAAAVV LQLMNIRRCG HSENFFFIEV GRSAVTGPGE FWMQVDDSVV 250 260 270 280 290 300 AQNMHETILE AMRAMSDEFR PRTKSQSSSS CSNPISVPLR RHHLNNPPPS QVGLTRRSRT 310 320 330 340 350 360 ESITATSPAS MVGGKPGSFR VRASSDGEGT MSRPASVDGS PVSPSTNRTH AHRHRGSSRL 370 380 390 400 410 420 HPPLNHSRSI PMPSSRCSPS ATSPVSLSSS STSGHGSTSD CLFPRRSSAS VSGSPSDGGF 430 440 450 460 470 480 ISSDEYGSSP CDFRSSFRSV TPDSLGHTPP ARGEEELSNY ICMGGKGAST LTAPNGHYIL 490 500 510 520 530 540 SRGGNGHRYI PGATMGTSPA LTGDEAAGAA DLDNRFRKRT HSAGTSPTIS HQKTPSQSSV 550 560 570 580 590 600 VSIEEYTEMM PAAYPPGGGS GGRLPGYRHS AFVPTHSYPE EGLEMHHLER RGGHHRPDSS 610 620 630 640 650 660 NLHTDDGYMP MSPGVAPVPS NRKGNGDYMP MSPKSVSAPQ QIINPIRRHP QRVDPNGYMM 670 680 690 700 710 720 MSPSGSCSPD IGGGSCSSSS ISAAPSGSSY GKPWTNGVGG HHTHALPHAK PPVESGGGKL 730 740 750 760 770 780 LPCTGDYMNM SPVGDSNTSS PSECYYGPED PQHKPVLSYY SLPRSFKHTQ RPGEPEEGAR 790 800 810 820 830 840 HQHLRLSSSS GRLRYTATAE DSSSSTSSDS LGGGYCGARP ESSVTHPHHH ALQPHLPRKV 850 860 870 880 890 900 DTAAQTNSRL ARPTRLSLGD PKASTLPRVR EQQQQQQQQQ QSSLHPPEPK SPGEYVNIEF 910 920 930 940 950 960 GSGQPGYLAG PATSRSSPSV RCLPQLHPAP REETGSEEYM NMDLGPGRRA TWQESGGVEL 970 980 990 1000 1010 1020 GRVGPAPPGA ASICRPTRSV PNSRGDYMTM QIGCPRQSYV DTSPVAPVSY ADMRTGIAAE 1030 1040 1050 1060 1070 1080 KVSLPRTTGA APPPSSTASA SASVTPQGAA EQAAHSSLLG GPQGPGGMSA FTRVNLSPNH 1090 1100 1110 1120 1130 1140 NQSAKVIRAD TQGCRRRHSS ETFSAPTRAA NTVSFGAGAA GGGSGGGSED VKRHSSASFE 1150 1160 1170 1180 1190 1200 NVWLRPGDLG GASKESAPGC GAAGGLEKSL NYIDLDLVKD VKQHPQDCPS QQQSLPPPPP 1210 1220 1230 HQPLGSNEGS SPRRSSEDLS TYASINFQKQ PEDRQ

References

[1]	"Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein." Sun X.-J., Rothenberg P.L., Kahn C.R., Backer J.M., Araki E., Wilden P.A., Cahill D.A., Goldstein B.J., White M.F. Nature 352:73-77(1991) [PubMed: 1648180] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE. Strain: Sprague-Dawley. Tissue: Liver.
[2]	"Purification and partial sequence analysis of pp185, the major cellular substrate of the insulin receptor tyrosine kinase." Rothenberg P.L., Lane W.S., Karasik A., Backer J.M., White M.F., Kahn C.R. J. Biol. Chem. 266:8302-8311(1991) [PubMed: 2022647] [Abstract] Cited for: PROTEIN SEQUENCE OF 44-51; 173-178; 223-243; 489-506; 635-646; 932-947 AND 1098-1106.
[3]	"Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation." Backer J.M., Myers M.G. Jr., Shoelson S.E., Chin D.J., Sun X.-J., Miralpeix M., Hu P., Margolis B., Skolnik E.Y., Schlessinger J., White M.F. EMBO J. 11:3469-3479(1992) [PubMed: 1380456] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION, INTERACTION WITH PIK3R1.
[4]	"The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling." Skolnik E.Y., Lee C.-H., Batzer A.G., Vicentini L.M., Zhou M., Daly R.J., Myers M.J. Jr., Backer J.M., Ullrich A., White M.F., Schlessinger J. EMBO J. 12:1929-1936(1993) [PubMed: 8491186] [Abstract] Cited for: INTERACTION WITH GRB2.
[5]	"Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1." Sun X.-J., Crimmins D.L., Myers M.G. Jr., Miralpeix M., White M.F. Mol. Cell. Biol. 13:7418-7428(1993) [PubMed: 7504175] [Abstract] Cited for: PHOSPHORYLATION AT TYR-460; TYR-608; TYR-895; TYR-939; TYR-987; TYR-1172 AND TYR-1222.
[6]	"Phosphorylation of the insulin receptor substrate IRS-1 by casein kinase II." Tanasijevic M.J., Myers M.G. Jr., Thoma R.S., Crimmins D.L., White M.F., Sacks D.B. J. Biol. Chem. 268:18157-18166(1993) [PubMed: 8349691] [Abstract] Cited for: PHOSPHORYLATION AT SER-99 AND THR-502.
[7]	"Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action." Aguirre V., Werner E.D., Giraud J., Lee Y.H., Shoelson S.E., White M.F. J. Biol. Chem. 277:1531-1537(2002) [PubMed: 11606564] [Abstract] Cited for: PHOSPHORYLATION AT SER-307.
[8]	"In vivo phosphorylation of insulin receptor substrate 1 at serine 789 by a novel serine kinase in insulin-resistant rodents." Qiao L.Y., Zhande R., Jetton T.L., Zhou G., Sun X.-J. J. Biol. Chem. 277:26530-26539(2002) [PubMed: 12006586] [Abstract] Cited for: PHOSPHORYLATION AT SER-789.
[9]	"Active Rho kinase (ROK-alpha) associates with insulin receptor substrate-1 and inhibits insulin signaling in vascular smooth muscle cells." Begum N., Sandu O.A., Ito M., Lohmann S.M., Smolenski A. J. Biol. Chem. 277:6214-6222(2002) [PubMed: 11739394] [Abstract] Cited for: INTERACTION WITH ROCK1, PHOSPHORYLATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	X58375 mRNA. Translation: CAA41264.1.
IPI	IPI00199662.
PIR	S16948.
RefSeq	NP_037101.1.
UniGene	Rn.10476
3D structure databases
HSSP	HSSP built from PDB template 1IRS based on UniProtKB P35568.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP:664N.
IntAct	P35570. 7 interactions.
STRING	P35570.
PTM databases
PhosphoSite	P35570.
Proteomic databases
PRIDE	P35570.
Genome annotation databases
Ensembl	ENSRNOT00000019579; ENSRNOP00000019579; ENSRNOG00000014597; Rattus norvegicus. [Genome view]
GeneID	25467.
KEGG	rno:25467.
UCSC	NM_012969. rat.
Organism-specific databases
CTD	25467.
RGD	2922. Irs1.
Phylogenomic databases
HOVERGEN	P35570.
Gene expression databases
Genevestigator	P35570.
Family and domain databases
InterPro	IPR002404. Insln_rcpt_S1. IPR011993. PH_type. IPR001849. Pleckstrin_homology. [Graphical view]
Gene3D	G3DSA:2.30.29.30. PH_type. 2 hits.
Pfam	PF02174. IRS. 1 hit. PF00169. PH. 1 hit. [Graphical view]
PRINTS	PR00628. INSULINRSI.
SMART	SM00233. PH. 1 hit. SM00310. PTBI. 1 hit. [Graphical view]
PROSITE	PS51064. IRS_PTB. 1 hit. PS50003. PH_DOMAIN. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	606757.

Entry information

Entry name

IRS1_RAT

Accession

Primary (citable) accession number: P35570

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 1, 1994
Last modified:	October 13, 2009
This is version 81 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)