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Protein

Growth factor receptor-bound protein 14

Gene

GRB14

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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

  • SH3/SH2 adaptor activity Source: ProtInc

GO - Biological processi

  • leukocyte migration Source: Reactome
  • signal transduction Source: ProtInc
Complete GO annotation...

Enzyme and pathway databases

BioCyciZFISH:ENSG00000115290-MONOMER.
ReactomeiR-HSA-210993. 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
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:4565. GRB14.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: BHF-UCL
  • cytosol Source: Reactome
  • endosome membrane Source: UniProtKB-SubCell
  • intracellular membrane-bounded organelle Source: BHF-UCL
  • plasma membrane Source: BHF-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi140K → A: Partial loss of INSR-binding. Loss of inhibition of AKT1 activation. Loss of inhibition of MAPK3 phosphorylation. Loss of NRAS-binding. 1 Publication1
Mutagenesisi245E → G: 4-fold increase in PI(3,4,5)P3-binding affinity; when associated with S-246. 1 Publication1
Mutagenesisi246Q → S: 4-fold increase in PI(3,4,5)P3-binding affinity; when associated with G-245. 1 Publication1
Mutagenesisi252K → 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 Publication1
Mutagenesisi299G → N: No effect on PI(3,4,5)P3-binding. 1 Publication1
Mutagenesisi348Q → 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 Publication1
Mutagenesisi349N → 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 Publication1

Organism-specific databases

DisGeNETi2888.
OpenTargetsiENSG00000115290.
PharmGKBiPA28961.

Polymorphism and mutation databases

BioMutaiGRB14.
DMDMi59802920.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00001503482 – 540Growth factor receptor-bound protein 14Add BLAST539

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylthreonineCombined sources1
Modified residuei372PhosphoserineBy similarity1
Modified residuei375PhosphoserineBy similarity1
Isoform 2 (identifier: Q14449-2)
Modified residuei9PhosphothreonineCombined sources1

Post-translational modificationi

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

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ14449.
MaxQBiQ14449.
PaxDbiQ14449.
PeptideAtlasiQ14449.
PRIDEiQ14449.

PTM databases

iPTMnetiQ14449.
PhosphoSitePlusiQ14449.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiENSG00000115290.
CleanExiHS_GRB14.
ExpressionAtlasiQ14449. baseline and differential.
GenevisibleiQ14449. HS.

Organism-specific databases

HPAiCAB022294.
HPA035052.
HPA035053.

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).By similarity5 Publications

GO - Molecular functioni

  • SH3/SH2 adaptor activity Source: ProtInc

Protein-protein interaction databases

BioGridi109145. 16 interactors.
DIPiDIP-42605N.
IntActiQ14449. 12 interactors.
MINTiMINT-1894128.
STRINGi9606.ENSP00000263915.

Structurei

Secondary structure

1540
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi107 – 113Combined sources7
Beta strandi119 – 125Combined sources7
Helixi130 – 141Combined sources12
Beta strandi149 – 155Combined sources7
Turni156 – 159Combined sources4
Beta strandi160 – 163Combined sources4
Helixi170 – 175Combined sources6
Beta strandi184 – 189Combined sources6
Helixi195 – 198Combined sources4
Turni201 – 203Combined sources3
Turni206 – 208Combined sources3
Helixi221 – 229Combined sources9
Beta strandi236 – 244Combined sources9
Beta strandi251 – 259Combined sources9
Beta strandi262 – 268Combined sources7
Turni274 – 276Combined sources3
Beta strandi277 – 281Combined sources5
Beta strandi283 – 291Combined sources9
Turni297 – 299Combined sources3
Beta strandi301 – 303Combined sources3
Beta strandi305 – 310Combined sources6
Beta strandi312 – 315Combined sources4
Beta strandi320 – 323Combined sources4
Helixi327 – 342Combined sources16
Helixi344 – 351Combined sources8
Beta strandi377 – 380Combined sources4
Beta strandi382 – 385Combined sources4
Helixi392 – 407Combined sources16
Helixi434 – 436Combined sources3
Helixi446 – 454Combined sources9
Turni455 – 457Combined sources3
Beta strandi462 – 467Combined sources6
Beta strandi469 – 472Combined sources4
Beta strandi475 – 481Combined sources7
Beta strandi484 – 495Combined sources12
Beta strandi498 – 504Combined sources7
Beta strandi510 – 512Combined sources3
Helixi513 – 520Combined sources8
Beta strandi527 – 529Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2AUGX-ray2.30A/B433-537[»]
2AUHX-ray3.20B361-419[»]
4K81X-ray2.40A/C/E/G106-356[»]
DisProtiDP00230.
ProteinModelPortaliQ14449.
SMRiQ14449.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ14449.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini106 – 192Ras-associatingPROSITE-ProRule annotationAdd BLAST87
Domaini234 – 342PHPROSITE-ProRule annotationAdd BLAST109
Domaini439 – 535SH2PROSITE-ProRule annotationAdd BLAST97

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.Curated
Contains 1 PH domain.PROSITE-ProRule annotation
Contains 1 Ras-associating domain.PROSITE-ProRule annotation
Contains 1 SH2 domain.PROSITE-ProRule annotation

Keywords - Domaini

SH2 domain

Phylogenomic databases

eggNOGiENOG410IQ4V. Eukaryota.
ENOG410ZN6J. LUCA.
GeneTreeiENSGT00550000074537.
HOGENOMiHOG000231904.
HOVERGENiHBG000468.
InParanoidiQ14449.
OMAiERIIEDH.
OrthoDBiEOG091G135G.
PhylomeDBiQ14449.
TreeFamiTF317511.

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
3.30.505.10. 1 hit.
InterProiIPR015042. BPS-dom.
IPR011993. PH_dom-like.
IPR001849. PH_domain.
IPR000159. RA_dom.
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]
SUPFAMiSSF50729. SSF50729. 1 hit.
SSF54236. SSF54236. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEiPS50003. PH_DOMAIN. 1 hit.
PS50200. RA. 1 hit.
PS50001. SH2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q14449-1) [UniParc]FASTAAdd to basket

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
MTTSLQDGQS AASRAAARDS PLAAQVCGAA QGRGDAHDLA PAPWLHARAL
60 70 80 90 100
LPLPDGTRGC AADRRKKKDL DVPEMPSIPN PFPELCCSPF TSVLSADLFP
110 120 130 140 150
KANSRKKQVI KVYSEDETSR ALDVPSDITA RDVCQLLILK NHYIDDHSWT
160 170 180 190 200
LFEHLPHIGV ERTIEDHELV IEVLSNWGIE EENKLYFRKN YAKYEFFKNP
210 220 230 240 250
MYFFPEHMVS FATETNGEIS PTQILQMFLS SSTYPEIHGF LHAKEQGKKS
260 270 280 290 300
WKKIYFFLRR SGLYFSTKGT SKEPRHLQFF SEFGNSDIYV SLAGKKKHGA
310 320 330 340 350
PTNYGFCFKP NKAGGPRDLK MLCAEEEQSR TCWVTAIRLL KYGMQLYQNY
360 370 380 390 400
MHPYQGRSGC SSQSISPMRS ISENSLVAMD FSGQKSRVIE NPTEALSVAV
410 420 430 440 450
EEGLAWRKKG CLRLGTHGSP TASSQSSATN MAIHRSQPWF HHKISRDEAQ
460 470 480 490 500
RLIIQQGLVD GVFLVRDSQS NPKTFVLSMS HGQKIKHFQI IPVEDDGEMF
510 520 530 540
HTLDDGHTRF TDLIQLVEFY QLNKGVLPCK LKHYCARIAL
Length:540
Mass (Da):60,988
Last modified:February 15, 2005 - v2
Checksum:i00472988650F7C6C
GO
Isoform 2 (identifier: Q14449-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-21: MTTSLQDGQSAASRAAARDSP → MSLSARRVTLPAITPIILQKR
     22-108: Missing.

Note: No experimental confirmation available.Combined sources
Show »
Length:453
Mass (Da):51,946
Checksum:i82469B04B7231E1C
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06575890F → I.2 PublicationsCorresponds to variant rs61748245dbSNPEnsembl.1
Natural variantiVAR_065759507H → Y in a patient with amyotrophic lateral sclerosis. 1 PublicationCorresponds to variant rs144301087dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0565821 – 21MTTSL…ARDSP → MSLSARRVTLPAITPIILQK R in isoform 2. 1 PublicationAdd BLAST21
Alternative sequenceiVSP_05658322 – 108Missing in isoform 2. 1 PublicationAdd BLAST87

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L76687 mRNA. Translation: AAC15861.1.
AK301961 mRNA. Translation: BAH13595.1.
AC107075 Genomic DNA. No translation available.
AC110086 Genomic DNA. No translation available.
CH471058 Genomic DNA. Translation: EAX11342.1.
BC053559 mRNA. Translation: AAH53559.1.
CCDSiCCDS2222.1. [Q14449-1]
RefSeqiNP_001290351.1. NM_001303422.1. [Q14449-2]
NP_004481.2. NM_004490.2. [Q14449-1]
UniGeneiHs.411881.

Genome annotation databases

EnsembliENST00000263915; ENSP00000263915; ENSG00000115290. [Q14449-1]
GeneIDi2888.
KEGGihsa:2888.
UCSCiuc002ucl.4. human. [Q14449-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L76687 mRNA. Translation: AAC15861.1.
AK301961 mRNA. Translation: BAH13595.1.
AC107075 Genomic DNA. No translation available.
AC110086 Genomic DNA. No translation available.
CH471058 Genomic DNA. Translation: EAX11342.1.
BC053559 mRNA. Translation: AAH53559.1.
CCDSiCCDS2222.1. [Q14449-1]
RefSeqiNP_001290351.1. NM_001303422.1. [Q14449-2]
NP_004481.2. NM_004490.2. [Q14449-1]
UniGeneiHs.411881.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2AUGX-ray2.30A/B433-537[»]
2AUHX-ray3.20B361-419[»]
4K81X-ray2.40A/C/E/G106-356[»]
DisProtiDP00230.
ProteinModelPortaliQ14449.
SMRiQ14449.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109145. 16 interactors.
DIPiDIP-42605N.
IntActiQ14449. 12 interactors.
MINTiMINT-1894128.
STRINGi9606.ENSP00000263915.

PTM databases

iPTMnetiQ14449.
PhosphoSitePlusiQ14449.

Polymorphism and mutation databases

BioMutaiGRB14.
DMDMi59802920.

Proteomic databases

EPDiQ14449.
MaxQBiQ14449.
PaxDbiQ14449.
PeptideAtlasiQ14449.
PRIDEiQ14449.

Protocols and materials databases

DNASUi2888.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000263915; ENSP00000263915; ENSG00000115290. [Q14449-1]
GeneIDi2888.
KEGGihsa:2888.
UCSCiuc002ucl.4. human. [Q14449-1]

Organism-specific databases

CTDi2888.
DisGeNETi2888.
GeneCardsiGRB14.
HGNCiHGNC:4565. GRB14.
HPAiCAB022294.
HPA035052.
HPA035053.
MIMi601524. gene.
neXtProtiNX_Q14449.
OpenTargetsiENSG00000115290.
PharmGKBiPA28961.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IQ4V. Eukaryota.
ENOG410ZN6J. LUCA.
GeneTreeiENSGT00550000074537.
HOGENOMiHOG000231904.
HOVERGENiHBG000468.
InParanoidiQ14449.
OMAiERIIEDH.
OrthoDBiEOG091G135G.
PhylomeDBiQ14449.
TreeFamiTF317511.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000115290-MONOMER.
ReactomeiR-HSA-210993. Tie2 Signaling.
SignaLinkiQ14449.

Miscellaneous databases

ChiTaRSiGRB14. human.
EvolutionaryTraceiQ14449.
GeneWikiiGRB14.
GenomeRNAii2888.
PROiQ14449.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000115290.
CleanExiHS_GRB14.
ExpressionAtlasiQ14449. baseline and differential.
GenevisibleiQ14449. HS.

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
3.30.505.10. 1 hit.
InterProiIPR015042. BPS-dom.
IPR011993. PH_dom-like.
IPR001849. PH_domain.
IPR000159. RA_dom.
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]
SUPFAMiSSF50729. SSF50729. 1 hit.
SSF54236. SSF54236. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEiPS50003. PH_DOMAIN. 1 hit.
PS50200. RA. 1 hit.
PS50001. SH2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiGRB14_HUMAN
AccessioniPrimary (citable) accession number: Q14449
Secondary accession number(s): B7Z7F9, Q7Z6I1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: February 15, 2005
Last modified: November 30, 2016
This is version 150 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

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.