Q14449 (GRB14_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Growth factor receptor-bound protein 14

Alternative name(s):
GRB14 adapter protein

Gene names

Name:

GRB14

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	540 AA.
Sequence status	Complete.
Protein existence	Evidence 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.5
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.5 Ref.7
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.5
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.5
Post-translational modification	Phosphorylated on serine residues. Phosphorylated on tyrosine residues by TEK/TIE2. Ref.7
Sequence similarities	Belongs to the GRB7/10/14 family. Contains 1 PH domain. Contains 1 Ras-associating domain. Contains 1 SH2 domain.

Ontologies

Keywords
Cellular component	Cytoplasm Endosome Golgi apparatus Membrane
Coding sequence diversity	Polymorphism
Domain	SH2 domain
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	blood coagulation Traceable author statement. Source: Reactome leukocyte migration Traceable author statement. Source: Reactome signal transduction Traceable author statement Ref.1. Source: ProtInc
Cellular_component	Golgi membrane Inferred from electronic annotation. Source: UniProtKB-SubCell cytosol Traceable author statement. Source: Reactome endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell intracellular membrane-bounded organelle Inferred from direct assay PubMed 11278563. Source: BHF-UCL plasma membrane Inferred from direct assay PubMed 11278563. Source: BHF-UCL
Molecular_function	SH3/SH2 adaptor activity Traceable author statement Ref.1. Source: ProtInc phospholipid binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 540

540

Growth factor receptor-bound protein 14

PRO_0000150348

Regions

Domain

106 – 192

87

Ras-associating

Domain

234 – 342

109

PH

Domain

439 – 535

97

SH2

Amino acid modifications

Modified residue

372

1

Phosphoserine By similarity

Natural variations

Natural variant

90

1

F → I. Ref.1 Ref.9
Corresponds to variant rs61748245 [ dbSNP | Ensembl ].

VAR_065758

Natural variant

507

1

H → Y in a patient with amyotrophic lateral sclerosis. Ref.9

VAR_065759

Experimental info

Mutagenesis

140

1

K → A: Partial loss of INSR-binding. Loss of inhibition of AKT1 activation. Loss of inhibition of MAPK3 phosphorylation. Loss of NRAS-binding. Ref.5

Mutagenesis

245

1

E → G: 4-fold increase in PI(3,4,5)P3-binding affinity; when associated with S-246. Ref.5

Mutagenesis

246

1

Q → S: 4-fold increase in PI(3,4,5)P3-binding affinity; when associated with G-245. Ref.5

Mutagenesis

252

1

K → 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.5

Mutagenesis

299

1

G → N: No effect on PI(3,4,5)P3-binding. Ref.5

Mutagenesis

348

1

Q → 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.5

Mutagenesis

349

1

N → 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.5

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

540

Helix Strand Turn

Details...

Beta strand

377 – 380

4

Beta strand

382 – 385

4

Helix

392 – 407

16

Helix

434 – 436

3

Helix

446 – 454

9

Turn

455 – 457

3

Beta strand

462 – 467

6

Beta strand

469 – 472

4

Beta strand

475 – 481

7

Beta strand

484 – 495

12

Beta strand

498 – 504

7

Beta strand

510 – 512

3

Helix

513 – 520

8

Beta strand

527 – 529

3

Sequences

	Sequence		Length	Mass (Da)
	Q14449 [UniParc]. Last modified February 15, 2005. Version 2. Checksum: 00472988650F7C6C	FASTA	540	60,988
	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

References

	« Hide 'large scale' referencesShow '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]	"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.
[6]	Erratum Depetris R.S., Wu J., Hubbard S.R. Nat. Struct. Mol. Biol. 16:1331-1331(2009)
[7]	"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.
[8]	"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.
[9]	"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.

IPI

IPI00030917.

RefSeq

NP_004481.2. NM_004490.2.

UniGene

Hs.411881.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2AUG	X-ray	2.30	A/B	433-537	[»]
2AUH	X-ray	3.20	B	361-419	[»]

DisProt

DP00230.

ProteinModelPortal

Q14449.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-42605N.

IntAct

Q14449. 3 interactions.

MINT

MINT-1894128.

STRING

9606.ENSP00000263915.

PTM databases

PhosphoSite

Q14449.

Polymorphism databases

DMDM

59802920.

Proteomic databases

PaxDb

Q14449.

PRIDE

Q14449.

Protocols and materials databases

DNASU

2888.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000263915; ENSP00000263915; ENSG00000115290.

GeneID

2888.

KEGG

hsa:2888.

UCSC

uc002ucl.3. human.

Organism-specific databases

CTD

2888.

GeneCards

GC02M165313.

HGNC

HGNC:4565. GRB14.

HPA

CAB022294.

MIM

601524. gene.

neXtProt

NX_Q14449.

PharmGKB

PA28961.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG307156.

HOGENOM

HOG000231904.

HOVERGEN

HBG000468.

InParanoid

Q14449.

OMA

HFQIIPV.

OrthoDB

EOG4N30NN.

PhylomeDB

Q14449.

Enzyme and pathway databases

Pathway_Interaction_DB

angiopoietinreceptor_pathway. Angiopoietin receptor Tie2-mediated signaling.
insulin_pathway. Insulin Pathway.

Reactome

REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

Q14449.

Bgee

Q14449.

CleanEx

HS_GRB14.

Genevestigator

Q14449.

GermOnline

ENSG00000115290. Homo sapiens.

Family and domain databases

Gene3D

2.30.29.30. 1 hit.
3.30.505.10. 1 hit.

InterPro

IPR015042. BPS-dom.
IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
IPR000159. Ras-assoc.
IPR000980. SH2.
[Graphical view]

Pfam

PF08947. BPS. 1 hit.
PF00169. PH. 1 hit.
PF00788. RA. 1 hit.
PF00017. SH2. 1 hit.
[Graphical view]

PRINTS

PR00401. SH2DOMAIN.

SMART

SM00233. PH. 1 hit.
SM00314. RA. 1 hit.
SM00252. SH2. 1 hit.
[Graphical view]

PROSITE

PS50003. PH_DOMAIN. 1 hit.
PS50200. RA. 1 hit.
PS50001. SH2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q14449.

GenomeRNAi

2888.

NextBio

11411.

SOURCE

Search...

Entry information

Entry name

GRB14_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 116 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.