ID GRB14_HUMAN Reviewed; 540 AA. AC Q14449; B7Z7F9; Q7Z6I1; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 15-FEB-2005, sequence version 2. DT 27-MAR-2024, entry version 196. DE RecName: Full=Growth factor receptor-bound protein 14; DE AltName: Full=GRB14 adapter protein; GN Name=GRB14; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ILE-90. RX PubMed=8647858; DOI=10.1074/jbc.271.21.12502; RA Daly R.J., Sanderson G.M., Janes P.W., Sutherland R.L.; RT "Cloning and characterization of GRB14, a novel member of the GRB7 gene RT family."; RL J. Biol. Chem. 271:12502-12510(1996). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP INTERACTION WITH INSR. RX PubMed=11726652; DOI=10.1074/jbc.m106574200; RA Bereziat V., Kasus-Jacobi A., Perdereau D., Cariou B., Girard J., RA Burnol A.F.; RT "Inhibition of insulin receptor catalytic activity by the molecular adapter RT Grb14."; RL J. Biol. Chem. 277:4845-4852(2002). RN [7] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PDPK1. RX PubMed=15210700; DOI=10.1074/jbc.m405340200; RA King C.C., Newton A.C.; RT "The adaptor protein Grb14 regulates the localization of 3- RT phosphoinositide-dependent kinase-1."; RL J. Biol. Chem. 279:37518-37527(2004). RN [8] RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [9] RP FUNCTION, INTERACTION WITH NRAS, PHOSPHOINOSITIDE-BINDING, SUBCELLULAR RP LOCATION, DOMAIN PH, AND MUTAGENESIS OF LYS-140; GLU-245; GLN-246; LYS-252; RP GLY-299; GLN-348 AND ASN-349. RX PubMed=19648926; DOI=10.1038/nsmb.1642; RA Depetris R.S., Wu J., Hubbard S.R.; RT "Structural and functional studies of the Ras-associating and pleckstrin- RT homology domains of Grb10 and Grb14."; RL Nat. Struct. Mol. Biol. 16:833-839(2009). RN [10] RP ERRATUM OF PUBMED:19648926. RA Depetris R.S., Wu J., Hubbard S.R.; RL Nat. Struct. Mol. Biol. 16:1331-1331(2009). RN [11] RP INTERACTION WITH TEK/TIE2, AND PHOSPHORYLATION. RX PubMed=20973951; DOI=10.1186/1478-811x-8-30; RA Sturk C., Dumont D.J.; RT "Tyrosine phosphorylation of Grb14 by Tie2."; RL Cell Commun. Signal. 8:30-30(2010). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-9 (ISOFORM 2), AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [13] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 361-419 AND 433-537 IN COMPLEX RP WITH INSR. RX PubMed=16246733; DOI=10.1016/j.molcel.2005.09.001; RA Depetris R.S., Hu J., Gimpelevich I., Holt L.J., Daly R.J., Hubbard S.R.; RT "Structural basis for inhibition of the insulin receptor by the adaptor RT protein Grb14."; RL Mol. Cell 20:325-333(2005). RN [14] RP VARIANTS ILE-90 AND TYR-507. RX PubMed=21220648; DOI=10.1001/archneurol.2010.351; RA Daoud H., Valdmanis P.N., Gros-Louis F., Belzil V., Spiegelman D., RA Henrion E., Diallo O., Desjarlais A., Gauthier J., Camu W., Dion P.A., RA Rouleau G.A.; RT "Resequencing of 29 candidate genes in patients with familial and sporadic RT amyotrophic lateral sclerosis."; RL Arch. Neurol. 68:587-593(2011). CC -!- FUNCTION: Adapter protein which modulates coupling of cell surface CC receptor kinases with specific signaling pathways. Binds to, and CC suppresses signals from, the activated insulin receptor (INSR). Potent CC inhibitor of insulin-stimulated MAPK3 phosphorylation. Plays a critical CC role regulating PDPK1 membrane translocation in response to insulin CC stimulation and serves as an adapter protein to recruit PDPK1 to CC activated insulin receptor, thus promoting PKB/AKT1 phosphorylation and CC transduction of the insulin signal. {ECO:0000269|PubMed:15210700, CC ECO:0000269|PubMed:19648926}. CC -!- SUBUNIT: Interacts with the cytoplasmic domain of the CC autophosphorylated insulin receptor (INSR), through the SH2 domain (By CC similarity). Interacts with GRB14 (via BPS domain); this interaction CC protects the tyrosines in the activation loop on INSR from CC dephosphorylation. Binds to the ankyrin repeat region of TNKS2 via its CC N-terminus. Interacts with activated NRAS. Interacts (via SH2 domain) CC with TEK/TIE2 (tyrosine phosphorylated). {ECO:0000250, CC ECO:0000269|PubMed:11726652, ECO:0000269|PubMed:15210700, CC ECO:0000269|PubMed:16246733, ECO:0000269|PubMed:19648926, CC ECO:0000269|PubMed:20973951}. CC -!- INTERACTION: CC Q14449; Q08379: GOLGA2; NbExp=3; IntAct=EBI-2680889, EBI-618309; CC Q14449; P14373: TRIM27; NbExp=3; IntAct=EBI-2680889, EBI-719493; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15210700, CC ECO:0000269|PubMed:19648926}. Endosome membrane CC {ECO:0000269|PubMed:15210700, ECO:0000269|PubMed:19648926}; Peripheral CC membrane protein {ECO:0000269|PubMed:15210700, CC ECO:0000269|PubMed:19648926}. Note=Upon insulin stimulation, CC translocates to the plasma membrane. {ECO:0000269|PubMed:15210700, CC ECO:0000269|PubMed:19648926}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q14449-1; Sequence=Displayed; CC Name=2; CC IsoId=Q14449-2; Sequence=VSP_056582, VSP_056583; CC -!- TISSUE SPECIFICITY: Expressed at high levels in the liver, kidney, CC pancreas, testis, ovary, heart and skeletal muscle. CC -!- DOMAIN: The PH domain binds relatively non-specifically and with low CC affinity to several phosphoinositides, the best binder being CC PI(3,4,5)P3. {ECO:0000269|PubMed:19648926}. CC -!- PTM: Phosphorylated on serine residues. Phosphorylated on tyrosine CC residues by TEK/TIE2. {ECO:0000269|PubMed:20973951}. CC -!- SIMILARITY: Belongs to the GRB7/10/14 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L76687; AAC15861.1; -; mRNA. DR EMBL; AK301961; BAH13595.1; -; mRNA. DR EMBL; AC107075; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC110086; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471058; EAX11342.1; -; Genomic_DNA. DR EMBL; BC053559; AAH53559.1; -; mRNA. DR CCDS; CCDS2222.1; -. [Q14449-1] DR CCDS; CCDS92883.1; -. [Q14449-2] DR RefSeq; NP_001290351.1; NM_001303422.1. [Q14449-2] DR RefSeq; NP_004481.2; NM_004490.2. [Q14449-1] DR PDB; 2AUG; X-ray; 2.30 A; A/B=433-537. DR PDB; 2AUH; X-ray; 3.20 A; B=361-419. DR PDB; 4K81; X-ray; 2.40 A; A/C/E/G=106-356. DR PDBsum; 2AUG; -. DR PDBsum; 2AUH; -. DR PDBsum; 4K81; -. DR AlphaFoldDB; Q14449; -. DR SMR; Q14449; -. DR BioGRID; 109145; 27. DR DIP; DIP-42605N; -. DR IntAct; Q14449; 13. DR MINT; Q14449; -. DR STRING; 9606.ENSP00000263915; -. DR GlyGen; Q14449; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q14449; -. DR PhosphoSitePlus; Q14449; -. DR BioMuta; GRB14; -. DR DMDM; 59802920; -. DR EPD; Q14449; -. DR MassIVE; Q14449; -. DR MaxQB; Q14449; -. DR PaxDb; 9606-ENSP00000263915; -. DR PeptideAtlas; Q14449; -. DR ProteomicsDB; 59994; -. [Q14449-1] DR ProteomicsDB; 6865; -. DR Pumba; Q14449; -. DR Antibodypedia; 33757; 215 antibodies from 29 providers. DR DNASU; 2888; -. DR Ensembl; ENST00000263915.8; ENSP00000263915.3; ENSG00000115290.11. [Q14449-1] DR Ensembl; ENST00000696453.2; ENSP00000512640.1; ENSG00000115290.11. [Q14449-2] DR GeneID; 2888; -. DR KEGG; hsa:2888; -. DR MANE-Select; ENST00000263915.8; ENSP00000263915.3; NM_004490.3; NP_004481.2. DR UCSC; uc002ucl.4; human. [Q14449-1] DR AGR; HGNC:4565; -. DR CTD; 2888; -. DR DisGeNET; 2888; -. DR GeneCards; GRB14; -. DR HGNC; HGNC:4565; GRB14. DR HPA; ENSG00000115290; Tissue enhanced (epididymis, liver, tongue). DR MIM; 601524; gene. DR neXtProt; NX_Q14449; -. DR OpenTargets; ENSG00000115290; -. DR PharmGKB; PA28961; -. DR VEuPathDB; HostDB:ENSG00000115290; -. DR eggNOG; KOG3751; Eukaryota. DR GeneTree; ENSGT00940000158609; -. DR HOGENOM; CLU_023207_0_1_1; -. DR InParanoid; Q14449; -. DR OMA; EDDGAMF; -. DR OrthoDB; 3144731at2759; -. DR PhylomeDB; Q14449; -. DR TreeFam; TF317511; -. DR PathwayCommons; Q14449; -. DR Reactome; R-HSA-210993; Tie2 Signaling. DR SignaLink; Q14449; -. DR SIGNOR; Q14449; -. DR BioGRID-ORCS; 2888; 8 hits in 1146 CRISPR screens. DR ChiTaRS; GRB14; human. DR EvolutionaryTrace; Q14449; -. DR GeneWiki; GRB14; -. DR GenomeRNAi; 2888; -. DR Pharos; Q14449; Tbio. DR PRO; PR:Q14449; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q14449; Protein. DR Bgee; ENSG00000115290; Expressed in adrenal tissue and 132 other cell types or tissues. DR ExpressionAtlas; Q14449; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL. DR GO; GO:0060090; F:molecular adaptor activity; EXP:DisProt. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IEA:Ensembl. DR GO; GO:0030971; F:receptor tyrosine kinase binding; IPI:CAFA. DR GO; GO:0008286; P:insulin receptor signaling pathway; IBA:GO_Central. DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IMP:CAFA. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR CDD; cd01259; PH_APBB1IP; 1. DR CDD; cd16139; RA_GRB14; 1. DR CDD; cd10414; SH2_Grb14; 1. DR DisProt; DP00230; -. DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1. DR Gene3D; 3.30.505.10; SH2 domain; 1. DR InterPro; IPR015042; BPS-dom. DR InterPro; IPR039664; GRB/APBB1IP. DR InterPro; IPR035034; Grb14_SH2. DR InterPro; IPR011993; PH-like_dom_sf. DR InterPro; IPR039665; PH_APBB1IP. DR InterPro; IPR001849; PH_domain. DR InterPro; IPR000159; RA_dom. DR InterPro; IPR000980; SH2. DR InterPro; IPR036860; SH2_dom_sf. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR PANTHER; PTHR11243; GROWTH FACTOR RECEPTOR-BOUND PROTEIN; 1. DR PANTHER; PTHR11243:SF22; GROWTH FACTOR RECEPTOR-BOUND PROTEIN 14; 1. DR Pfam; PF08947; BPS; 1. DR Pfam; PF00169; PH; 1. DR Pfam; PF00788; RA; 1. DR Pfam; PF00017; SH2; 1. DR PRINTS; PR00401; SH2DOMAIN. DR SMART; SM00233; PH; 1. DR SMART; SM00314; RA; 1. DR SMART; SM00252; SH2; 1. DR SUPFAM; SSF50729; PH domain-like; 1. DR SUPFAM; SSF55550; SH2 domain; 1. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR PROSITE; PS50003; PH_DOMAIN; 1. DR PROSITE; PS50200; RA; 1. DR PROSITE; PS50001; SH2; 1. DR Genevisible; Q14449; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Cytoplasm; Endosome; KW Membrane; Phosphoprotein; Reference proteome; SH2 domain. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:19413330" FT CHAIN 2..540 FT /note="Growth factor receptor-bound protein 14" FT /id="PRO_0000150348" FT DOMAIN 106..192 FT /note="Ras-associating" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00166" FT DOMAIN 234..342 FT /note="PH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145" FT DOMAIN 439..535 FT /note="SH2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191" FT MOD_RES 2 FT /note="N-acetylthreonine" FT /evidence="ECO:0007744|PubMed:19413330" FT MOD_RES 372 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O88900" FT MOD_RES 375 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9JLM9" FT VAR_SEQ 1..21 FT /note="MTTSLQDGQSAASRAAARDSP -> MSLSARRVTLPAITPIILQKR (in FT isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056582" FT VAR_SEQ 22..108 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056583" FT VARIANT 90 FT /note="F -> I (in dbSNP:rs61748245)" FT /evidence="ECO:0000269|PubMed:21220648, FT ECO:0000269|PubMed:8647858" FT /id="VAR_065758" FT VARIANT 507 FT /note="H -> Y (in a patient with amyotrophic lateral FT sclerosis; dbSNP:rs144301087)" FT /evidence="ECO:0000269|PubMed:21220648" FT /id="VAR_065759" FT MUTAGEN 140 FT /note="K->A: Partial loss of INSR-binding. Loss of FT inhibition of AKT1 activation. Loss of inhibition of MAPK3 FT phosphorylation. Loss of NRAS-binding." FT /evidence="ECO:0000269|PubMed:19648926" FT MUTAGEN 245 FT /note="E->G: 4-fold increase in PI(3,4,5)P3-binding FT affinity; when associated with S-246." FT /evidence="ECO:0000269|PubMed:19648926" FT MUTAGEN 246 FT /note="Q->S: 4-fold increase in PI(3,4,5)P3-binding FT affinity; when associated with G-245." FT /evidence="ECO:0000269|PubMed:19648926" FT MUTAGEN 252 FT /note="K->A: Partial loss of INSR-binding. Loss of FT inhibition of AKT1 activation. Loss of inhibition of MAPK3 FT phosphorylation. Loss of translocation to the plasma FT membrane upon insulin-stimulation. More than 3-fold FT decrease in PI(3,4,5)P3-binding affinity." FT /evidence="ECO:0000269|PubMed:19648926" FT MUTAGEN 299 FT /note="G->N: No effect on PI(3,4,5)P3-binding." FT /evidence="ECO:0000269|PubMed:19648926" FT MUTAGEN 348 FT /note="Q->A: Loss of inhibition of AKT1 activation; when FT associated with A-349. Loss of inhibition of MAPK3 FT phosphorylation; when associated with A-349. No effect on FT INSR-binding; when associated with A-349." FT /evidence="ECO:0000269|PubMed:19648926" FT MUTAGEN 349 FT /note="N->A: Loss of inhibition of AKT1 activation; when FT associated with A-348. Loss of inhibition of MAPK3 FT phosphorylation; when associated with A-348. No effect on FT INSR-binding; when associated with A-348." FT /evidence="ECO:0000269|PubMed:19648926" FT STRAND 107..113 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 119..125 FT /evidence="ECO:0007829|PDB:4K81" FT HELIX 130..141 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 149..155 FT /evidence="ECO:0007829|PDB:4K81" FT TURN 156..159 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 160..163 FT /evidence="ECO:0007829|PDB:4K81" FT HELIX 170..175 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 184..189 FT /evidence="ECO:0007829|PDB:4K81" FT HELIX 195..198 FT /evidence="ECO:0007829|PDB:4K81" FT TURN 201..203 FT /evidence="ECO:0007829|PDB:4K81" FT TURN 206..208 FT /evidence="ECO:0007829|PDB:4K81" FT HELIX 221..229 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 236..244 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 251..259 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 262..268 FT /evidence="ECO:0007829|PDB:4K81" FT TURN 274..276 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 277..281 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 283..291 FT /evidence="ECO:0007829|PDB:4K81" FT TURN 297..299 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 301..303 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 305..310 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 312..315 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 320..323 FT /evidence="ECO:0007829|PDB:4K81" FT HELIX 327..342 FT /evidence="ECO:0007829|PDB:4K81" FT HELIX 344..351 FT /evidence="ECO:0007829|PDB:4K81" FT STRAND 377..380 FT /evidence="ECO:0007829|PDB:2AUH" FT STRAND 382..385 FT /evidence="ECO:0007829|PDB:2AUH" FT HELIX 392..407 FT /evidence="ECO:0007829|PDB:2AUH" FT HELIX 434..436 FT /evidence="ECO:0007829|PDB:2AUG" FT HELIX 446..454 FT /evidence="ECO:0007829|PDB:2AUG" FT TURN 455..457 FT /evidence="ECO:0007829|PDB:2AUG" FT STRAND 462..467 FT /evidence="ECO:0007829|PDB:2AUG" FT STRAND 469..472 FT /evidence="ECO:0007829|PDB:2AUG" FT STRAND 475..481 FT /evidence="ECO:0007829|PDB:2AUG" FT STRAND 484..495 FT /evidence="ECO:0007829|PDB:2AUG" FT STRAND 498..504 FT /evidence="ECO:0007829|PDB:2AUG" FT STRAND 510..512 FT /evidence="ECO:0007829|PDB:2AUG" FT HELIX 513..520 FT /evidence="ECO:0007829|PDB:2AUG" FT STRAND 527..529 FT /evidence="ECO:0007829|PDB:2AUG" FT MOD_RES Q14449-2:9 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:24275569" SQ SEQUENCE 540 AA; 60988 MW; 00472988650F7C6C CRC64; MTTSLQDGQS AASRAAARDS PLAAQVCGAA QGRGDAHDLA PAPWLHARAL LPLPDGTRGC AADRRKKKDL DVPEMPSIPN PFPELCCSPF TSVLSADLFP KANSRKKQVI KVYSEDETSR ALDVPSDITA RDVCQLLILK NHYIDDHSWT LFEHLPHIGV ERTIEDHELV IEVLSNWGIE EENKLYFRKN YAKYEFFKNP MYFFPEHMVS FATETNGEIS PTQILQMFLS SSTYPEIHGF LHAKEQGKKS WKKIYFFLRR SGLYFSTKGT SKEPRHLQFF SEFGNSDIYV SLAGKKKHGA PTNYGFCFKP NKAGGPRDLK MLCAEEEQSR TCWVTAIRLL KYGMQLYQNY MHPYQGRSGC SSQSISPMRS ISENSLVAMD FSGQKSRVIE NPTEALSVAV EEGLAWRKKG CLRLGTHGSP TASSQSSATN MAIHRSQPWF HHKISRDEAQ RLIIQQGLVD GVFLVRDSQS NPKTFVLSMS HGQKIKHFQI IPVEDDGEMF HTLDDGHTRF TDLIQLVEFY QLNKGVLPCK LKHYCARIAL //