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Q14449 (GRB14_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 125. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Growth factor receptor-bound protein 14
Alternative name(s):
GRB14 adapter protein
Gene names
Name:GRB14
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length540 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.4 Ref.6

Subunit structure

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). Ref.3 Ref.4 Ref.6 Ref.8

Subcellular location

Cytoplasm. Golgi apparatus membrane; Peripheral membrane protein. Endosome membrane; Peripheral membrane protein. Note: Upon insulin stimulation, translocates to the plasma membrane. Ref.4 Ref.6

Tissue specificity

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

Domain

The PH domain binds relatively non-specifically and with low affinity to several phosphoinositides, the best binder being PI(3,4,5)P3. Ref.6

Post-translational modification

Phosphorylated on serine residues. Phosphorylated on tyrosine residues by TEK/TIE2. Ref.8

Sequence similarities

Belongs to the GRB7/10/14 family.

Contains 1 PH domain.

Contains 1 Ras-associating domain.

Contains 1 SH2 domain.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.5
Chain2 – 540539Growth factor receptor-bound protein 14
PRO_0000150348

Regions

Domain106 – 19287Ras-associating
Domain234 – 342109PH
Domain439 – 53597SH2

Amino acid modifications

Modified residue21N-acetylthreonine Ref.5

Natural variations

Natural variant901F → I. Ref.1 Ref.10
Corresponds to variant rs61748245 [ dbSNP | Ensembl ].
VAR_065758
Natural variant5071H → Y in a patient with amyotrophic lateral sclerosis. Ref.10
VAR_065759

Experimental info

Mutagenesis1401K → A: Partial loss of INSR-binding. Loss of inhibition of AKT1 activation. Loss of inhibition of MAPK3 phosphorylation. Loss of NRAS-binding. Ref.6
Mutagenesis2451E → G: 4-fold increase in PI(3,4,5)P3-binding affinity; when associated with S-246. Ref.6
Mutagenesis2461Q → S: 4-fold increase in PI(3,4,5)P3-binding affinity; when associated with G-245. Ref.6
Mutagenesis2521K → 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. Ref.6
Mutagenesis2991G → N: No effect on PI(3,4,5)P3-binding. Ref.6
Mutagenesis3481Q → 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. Ref.6
Mutagenesis3491N → 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. Ref.6

Secondary structure

.......................................................................... 540
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q14449 [UniParc].

Last modified February 15, 2005. Version 2.
Checksum: 00472988650F7C6C

FASTA54060,988
        10         20         30         40         50         60 
MTTSLQDGQS AASRAAARDS PLAAQVCGAA QGRGDAHDLA PAPWLHARAL LPLPDGTRGC 

        70         80         90        100        110        120 
AADRRKKKDL DVPEMPSIPN PFPELCCSPF TSVLSADLFP KANSRKKQVI KVYSEDETSR 

       130        140        150        160        170        180 
ALDVPSDITA RDVCQLLILK NHYIDDHSWT LFEHLPHIGV ERTIEDHELV IEVLSNWGIE 

       190        200        210        220        230        240 
EENKLYFRKN YAKYEFFKNP MYFFPEHMVS FATETNGEIS PTQILQMFLS SSTYPEIHGF 

       250        260        270        280        290        300 
LHAKEQGKKS WKKIYFFLRR SGLYFSTKGT SKEPRHLQFF SEFGNSDIYV SLAGKKKHGA 

       310        320        330        340        350        360 
PTNYGFCFKP NKAGGPRDLK MLCAEEEQSR TCWVTAIRLL KYGMQLYQNY MHPYQGRSGC 

       370        380        390        400        410        420 
SSQSISPMRS ISENSLVAMD FSGQKSRVIE NPTEALSVAV EEGLAWRKKG CLRLGTHGSP 

       430        440        450        460        470        480 
TASSQSSATN MAIHRSQPWF HHKISRDEAQ RLIIQQGLVD GVFLVRDSQS NPKTFVLSMS 

       490        500        510        520        530        540 
HGQKIKHFQI IPVEDDGEMF HTLDDGHTRF TDLIQLVEFY QLNKGVLPCK LKHYCARIAL 

« Hide

References

« Hide 'large scale' references
[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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L76687 mRNA. Translation: AAC15861.1.
BC053559 mRNA. Translation: AAH53559.1.
RefSeqNP_004481.2. NM_004490.2.
UniGeneHs.411881.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2AUGX-ray2.30A/B433-537[»]
2AUHX-ray3.20B361-419[»]
4K81X-ray2.40A/C/E/G106-356[»]
DisProtDP00230.
ProteinModelPortalQ14449.
SMRQ14449. Positions 106-356, 373-537.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109145. 10 interactions.
DIPDIP-42605N.
IntActQ14449. 4 interactions.
MINTMINT-1894128.
STRING9606.ENSP00000263915.

PTM databases

PhosphoSiteQ14449.

Polymorphism databases

DMDM59802920.

Proteomic databases

PaxDbQ14449.
PRIDEQ14449.

Protocols and materials databases

DNASU2888.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000263915; ENSP00000263915; ENSG00000115290.
GeneID2888.
KEGGhsa:2888.
UCSCuc002ucl.3. human.

Organism-specific databases

CTD2888.
GeneCardsGC02M165313.
HGNCHGNC:4565. GRB14.
HPACAB022294.
HPA035052.
MIM601524. gene.
neXtProtNX_Q14449.
PharmGKBPA28961.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG307156.
HOGENOMHOG000231904.
HOVERGENHBG000468.
InParanoidQ14449.
OMAKLKHYCA.
OrthoDBEOG7SFHW7.
PhylomeDBQ14449.
TreeFamTF317511.

Enzyme and pathway databases

ReactomeREACT_604. Hemostasis.
SignaLinkQ14449.

Gene expression databases

ArrayExpressQ14449.
BgeeQ14449.
CleanExHS_GRB14.
GenevestigatorQ14449.

Family and domain databases

Gene3D2.30.29.30. 1 hit.
3.30.505.10. 1 hit.
InterProIPR015042. BPS-dom.
IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
IPR000159. Ras-assoc.
IPR000980. SH2.
[Graphical view]
PfamPF08947. BPS. 1 hit.
PF00169. PH. 1 hit.
PF00788. RA. 1 hit.
PF00017. SH2. 1 hit.
[Graphical view]
PRINTSPR00401. SH2DOMAIN.
SMARTSM00233. PH. 1 hit.
SM00314. RA. 1 hit.
SM00252. SH2. 1 hit.
[Graphical view]
SUPFAMSSF55550. SSF55550. 1 hit.
PROSITEPS50003. PH_DOMAIN. 1 hit.
PS50200. RA. 1 hit.
PS50001. SH2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ14449.
GeneWikiGRB14.
GenomeRNAi2888.
NextBio11411.
PROQ14449.
SOURCESearch...

Entry information

Entry nameGRB14_HUMAN
AccessionPrimary (citable) accession number: Q14449
Secondary accession number(s): Q7Z6I1
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: February 15, 2005
Last modified: April 16, 2014
This is version 125 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM