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Q14449

- GRB14_HUMAN

UniProt

Q14449 - GRB14_HUMAN

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Protein

Growth factor receptor-bound protein 14

Gene
GRB14
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

Adapter protein which modulates coupling of cell surface receptor kinases with specific signaling pathways. Binds to, and suppresses signals from, the activated insulin receptor (INSR). Potent inhibitor of insulin-stimulated MAPK3 phosphorylation. Plays a critical role regulating PDPK1 membrane translocation in response to insulin stimulation and serves as an adapter protein to recruit PDPK1 to activated insulin receptor, thus promoting PKB/AKT1 phosphorylation and transduction of the insulin signal.2 Publications

GO - Molecular functioni

  1. SH3/SH2 adaptor activity Source: ProtInc

GO - Biological processi

  1. blood coagulation Source: Reactome
  2. leukocyte migration Source: Reactome
  3. positive regulation of signal transduction Source: GOC
  4. signal transduction Source: ProtInc
Complete GO annotation...

Enzyme and pathway databases

ReactomeiREACT_12621. Tie2 Signaling.
SignaLinkiQ14449.

Names & Taxonomyi

Protein namesi
Recommended name:
Growth factor receptor-bound protein 14
Alternative name(s):
GRB14 adapter protein
Gene namesi
Name:GRB14
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 2

Organism-specific databases

HGNCiHGNC:4565. GRB14.

Subcellular locationi

Cytoplasm. Golgi apparatus membrane; Peripheral membrane protein. Endosome membrane; Peripheral membrane protein
Note: Upon insulin stimulation, translocates to the plasma membrane.2 Publications

GO - Cellular componenti

  1. cytoplasm Source: BHF-UCL
  2. cytosol Source: Reactome
  3. endosome membrane Source: UniProtKB-SubCell
  4. Golgi membrane Source: UniProtKB-SubCell
  5. intracellular membrane-bounded organelle Source: BHF-UCL
  6. plasma membrane Source: BHF-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endosome, Golgi apparatus, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi140 – 1401K → A: Partial loss of INSR-binding. Loss of inhibition of AKT1 activation. Loss of inhibition of MAPK3 phosphorylation. Loss of NRAS-binding. 1 Publication
Mutagenesisi245 – 2451E → G: 4-fold increase in PI(3,4,5)P3-binding affinity; when associated with S-246. 1 Publication
Mutagenesisi246 – 2461Q → S: 4-fold increase in PI(3,4,5)P3-binding affinity; when associated with G-245. 1 Publication
Mutagenesisi252 – 2521K → A: Partial loss of INSR-binding. Loss of inhibition of AKT1 activation. Loss of inhibition of MAPK3 phosphorylation. Loss of translocation to the plasma membrane upon insulin-stimulation. More than 3-fold decrease in PI(3,4,5)P3-binding affinity. 1 Publication
Mutagenesisi299 – 2991G → N: No effect on PI(3,4,5)P3-binding. 1 Publication
Mutagenesisi348 – 3481Q → A: Loss of inhibition of AKT1 activation; when associated with A-349. Loss of inhibition of MAPK3 phosphorylation; when associated with A-349. No effect on INSR-binding; when associated with A-349. 1 Publication
Mutagenesisi349 – 3491N → A: Loss of inhibition of AKT1 activation; when associated with A-348. Loss of inhibition of MAPK3 phosphorylation; when associated with A-348. No effect on INSR-binding; when associated with A-348. 1 Publication

Organism-specific databases

PharmGKBiPA28961.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed1 Publication
Chaini2 – 540539Growth factor receptor-bound protein 14PRO_0000150348Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylthreonine1 Publication

Post-translational modificationi

Phosphorylated on serine residues. Phosphorylated on tyrosine residues by TEK/TIE2.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiQ14449.
PaxDbiQ14449.
PRIDEiQ14449.

PTM databases

PhosphoSiteiQ14449.

Expressioni

Tissue specificityi

Expressed at high levels in the liver, kidney, pancreas, testis, ovary, heart and skeletal muscle.

Gene expression databases

ArrayExpressiQ14449.
BgeeiQ14449.
CleanExiHS_GRB14.
GenevestigatoriQ14449.

Organism-specific databases

HPAiCAB022294.
HPA035052.

Interactioni

Subunit structurei

Interacts with the cytoplasmic domain of the autophosphorylated insulin receptor (INSR), through the SH2 domain By similarity. Interacts with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop on INSR from dephosphorylation. Binds to the ankyrin repeat region of TNKS2 via its N-terminus. Interacts with activated NRAS. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated).4 Publications

Protein-protein interaction databases

BioGridi109145. 10 interactions.
DIPiDIP-42605N.
IntActiQ14449. 5 interactions.
MINTiMINT-1894128.
STRINGi9606.ENSP00000263915.

Structurei

Secondary structure

1
540
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi107 – 1137
Beta strandi119 – 1257
Helixi130 – 14112
Beta strandi149 – 1557
Turni156 – 1594
Beta strandi160 – 1634
Helixi170 – 1756
Beta strandi184 – 1896
Helixi195 – 1984
Turni201 – 2033
Turni206 – 2083
Helixi221 – 2299
Beta strandi236 – 2449
Beta strandi251 – 2599
Beta strandi262 – 2687
Turni274 – 2763
Beta strandi277 – 2815
Beta strandi283 – 2919
Turni297 – 2993
Beta strandi301 – 3033
Beta strandi305 – 3106
Beta strandi312 – 3154
Beta strandi320 – 3234
Helixi327 – 34216
Helixi344 – 3518
Beta strandi377 – 3804
Beta strandi382 – 3854
Helixi392 – 40716
Helixi434 – 4363
Helixi446 – 4549
Turni455 – 4573
Beta strandi462 – 4676
Beta strandi469 – 4724
Beta strandi475 – 4817
Beta strandi484 – 49512
Beta strandi498 – 5047
Beta strandi510 – 5123
Helixi513 – 5208
Beta strandi527 – 5293

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2AUGX-ray2.30A/B433-537[»]
2AUHX-ray3.20B361-419[»]
4K81X-ray2.40A/C/E/G106-356[»]
DisProtiDP00230.
ProteinModelPortaliQ14449.
SMRiQ14449. Positions 106-356, 373-537.

Miscellaneous databases

EvolutionaryTraceiQ14449.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini106 – 19287Ras-associatingAdd
BLAST
Domaini234 – 342109PHAdd
BLAST
Domaini439 – 53597SH2Add
BLAST

Domaini

The PH domain binds relatively non-specifically and with low affinity to several phosphoinositides, the best binder being PI(3,4,5)P3.1 Publication

Sequence similaritiesi

Belongs to the GRB7/10/14 family.
Contains 1 PH domain.
Contains 1 SH2 domain.

Keywords - Domaini

SH2 domain

Phylogenomic databases

eggNOGiNOG307156.
HOGENOMiHOG000231904.
HOVERGENiHBG000468.
InParanoidiQ14449.
OMAiKLKHYCA.
OrthoDBiEOG7SFHW7.
PhylomeDBiQ14449.
TreeFamiTF317511.

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
3.30.505.10. 1 hit.
InterProiIPR015042. BPS-dom.
IPR001849. PH_domain.
IPR011993. PH_like_dom.
IPR000159. Ras-assoc.
IPR000980. SH2.
IPR029071. Ubiquitin-rel_dom.
[Graphical view]
PfamiPF08947. BPS. 1 hit.
PF00169. PH. 1 hit.
PF00788. RA. 1 hit.
PF00017. SH2. 1 hit.
[Graphical view]
PRINTSiPR00401. SH2DOMAIN.
SMARTiSM00233. PH. 1 hit.
SM00314. RA. 1 hit.
SM00252. SH2. 1 hit.
[Graphical view]
SUPFAMiSSF54236. SSF54236. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEiPS50003. PH_DOMAIN. 1 hit.
PS50200. RA. 1 hit.
PS50001. SH2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q14449-1 [UniParc]FASTAAdd to Basket

« Hide

MTTSLQDGQS AASRAAARDS PLAAQVCGAA QGRGDAHDLA PAPWLHARAL    50
LPLPDGTRGC AADRRKKKDL DVPEMPSIPN PFPELCCSPF TSVLSADLFP 100
KANSRKKQVI KVYSEDETSR ALDVPSDITA RDVCQLLILK NHYIDDHSWT 150
LFEHLPHIGV ERTIEDHELV IEVLSNWGIE EENKLYFRKN YAKYEFFKNP 200
MYFFPEHMVS FATETNGEIS PTQILQMFLS SSTYPEIHGF LHAKEQGKKS 250
WKKIYFFLRR SGLYFSTKGT SKEPRHLQFF SEFGNSDIYV SLAGKKKHGA 300
PTNYGFCFKP NKAGGPRDLK MLCAEEEQSR TCWVTAIRLL KYGMQLYQNY 350
MHPYQGRSGC SSQSISPMRS ISENSLVAMD FSGQKSRVIE NPTEALSVAV 400
EEGLAWRKKG CLRLGTHGSP TASSQSSATN MAIHRSQPWF HHKISRDEAQ 450
RLIIQQGLVD GVFLVRDSQS NPKTFVLSMS HGQKIKHFQI IPVEDDGEMF 500
HTLDDGHTRF TDLIQLVEFY QLNKGVLPCK LKHYCARIAL 540
Length:540
Mass (Da):60,988
Last modified:February 15, 2005 - v2
Checksum:i00472988650F7C6C
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti90 – 901F → I.2 Publications
Corresponds to variant rs61748245 [ dbSNP | Ensembl ].
VAR_065758
Natural varianti507 – 5071H → Y in a patient with amyotrophic lateral sclerosis. 1 Publication
VAR_065759

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
L76687 mRNA. Translation: AAC15861.1.
BC053559 mRNA. Translation: AAH53559.1.
CCDSiCCDS2222.1.
RefSeqiNP_004481.2. NM_004490.2.
UniGeneiHs.411881.

Genome annotation databases

EnsembliENST00000263915; ENSP00000263915; ENSG00000115290.
GeneIDi2888.
KEGGihsa:2888.
UCSCiuc002ucl.3. human.

Polymorphism databases

DMDMi59802920.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
L76687 mRNA. Translation: AAC15861.1 .
BC053559 mRNA. Translation: AAH53559.1 .
CCDSi CCDS2222.1.
RefSeqi NP_004481.2. NM_004490.2.
UniGenei Hs.411881.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
2AUG X-ray 2.30 A/B 433-537 [» ]
2AUH X-ray 3.20 B 361-419 [» ]
4K81 X-ray 2.40 A/C/E/G 106-356 [» ]
DisProti DP00230.
ProteinModelPortali Q14449.
SMRi Q14449. Positions 106-356, 373-537.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 109145. 10 interactions.
DIPi DIP-42605N.
IntActi Q14449. 5 interactions.
MINTi MINT-1894128.
STRINGi 9606.ENSP00000263915.

PTM databases

PhosphoSitei Q14449.

Polymorphism databases

DMDMi 59802920.

Proteomic databases

MaxQBi Q14449.
PaxDbi Q14449.
PRIDEi Q14449.

Protocols and materials databases

DNASUi 2888.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000263915 ; ENSP00000263915 ; ENSG00000115290 .
GeneIDi 2888.
KEGGi hsa:2888.
UCSCi uc002ucl.3. human.

Organism-specific databases

CTDi 2888.
GeneCardsi GC02M165313.
HGNCi HGNC:4565. GRB14.
HPAi CAB022294.
HPA035052.
MIMi 601524. gene.
neXtProti NX_Q14449.
PharmGKBi PA28961.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG307156.
HOGENOMi HOG000231904.
HOVERGENi HBG000468.
InParanoidi Q14449.
OMAi KLKHYCA.
OrthoDBi EOG7SFHW7.
PhylomeDBi Q14449.
TreeFami TF317511.

Enzyme and pathway databases

Reactomei REACT_12621. Tie2 Signaling.
SignaLinki Q14449.

Miscellaneous databases

EvolutionaryTracei Q14449.
GeneWikii GRB14.
GenomeRNAii 2888.
NextBioi 11411.
PROi Q14449.
SOURCEi Search...

Gene expression databases

ArrayExpressi Q14449.
Bgeei Q14449.
CleanExi HS_GRB14.
Genevestigatori Q14449.

Family and domain databases

Gene3Di 2.30.29.30. 1 hit.
3.30.505.10. 1 hit.
InterProi IPR015042. BPS-dom.
IPR001849. PH_domain.
IPR011993. PH_like_dom.
IPR000159. Ras-assoc.
IPR000980. SH2.
IPR029071. Ubiquitin-rel_dom.
[Graphical view ]
Pfami PF08947. BPS. 1 hit.
PF00169. PH. 1 hit.
PF00788. RA. 1 hit.
PF00017. SH2. 1 hit.
[Graphical view ]
PRINTSi PR00401. SH2DOMAIN.
SMARTi SM00233. PH. 1 hit.
SM00314. RA. 1 hit.
SM00252. SH2. 1 hit.
[Graphical view ]
SUPFAMi SSF54236. SSF54236. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEi PS50003. PH_DOMAIN. 1 hit.
PS50200. RA. 1 hit.
PS50001. SH2. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Cloning and characterization of GRB14, a novel member of the GRB7 gene family."
    Daly R.J., Sanderson G.M., Janes P.W., Sutherland R.L.
    J. Biol. Chem. 271:12502-12510(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ILE-90.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Skin.
  3. "Inhibition of insulin receptor catalytic activity by the molecular adapter Grb14."
    Bereziat V., Kasus-Jacobi A., Perdereau D., Cariou B., Girard J., Burnol A.F.
    J. Biol. Chem. 277:4845-4852(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH INSR.
  4. "The adaptor protein Grb14 regulates the localization of 3-phosphoinositide-dependent kinase-1."
    King C.C., Newton A.C.
    J. Biol. Chem. 279:37518-37527(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PDPK1.
  5. "Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
    Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
    Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT THR-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
  6. "Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14."
    Depetris R.S., Wu J., Hubbard S.R.
    Nat. Struct. Mol. Biol. 16:833-839(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH NRAS, PHOSPHOINOSITIDE-BINDING, SUBCELLULAR LOCATION, DOMAIN PH, MUTAGENESIS OF LYS-140; GLU-245; GLN-246; LYS-252; GLY-299; GLN-348 AND ASN-349.
  7. Erratum
    Depetris R.S., Wu J., Hubbard S.R.
    Nat. Struct. Mol. Biol. 16:1331-1331(2009)
  8. "Tyrosine phosphorylation of Grb14 by Tie2."
    Sturk C., Dumont D.J.
    Cell Commun. Signal. 8:30-30(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH TEK/TIE2, PHOSPHORYLATION.
  9. "Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14."
    Depetris R.S., Hu J., Gimpelevich I., Holt L.J., Daly R.J., Hubbard S.R.
    Mol. Cell 20:325-333(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 361-419 AND 433-537 IN COMPLEX WITH INSR.
  10. "Resequencing of 29 candidate genes in patients with familial and sporadic amyotrophic lateral sclerosis."
    Daoud H., Valdmanis P.N., Gros-Louis F., Belzil V., Spiegelman D., Henrion E., Diallo O., Desjarlais A., Gauthier J., Camu W., Dion P.A., Rouleau G.A.
    Arch. Neurol. 68:587-593(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS ILE-90 AND TYR-507.

Entry informationi

Entry nameiGRB14_HUMAN
AccessioniPrimary (citable) accession number: Q14449
Secondary accession number(s): Q7Z6I1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: February 15, 2005
Last modified: September 3, 2014
This is version 129 of the entry and version 2 of the sequence. [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

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: 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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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