GRB2
entrez
2885
canonical
uniprot
P62993
canonical
ensembl
ENSG00000177885
resolver
ensp
ENSP00000317360
resolver
ensp
ENSP00000339007
resolver
genesymbol
GRB2
resolver
genesymbol_syn
ASH
resolver
hgnc
HGNC:4566
resolver
uniprot
B0LPF3
resolver
uniprot
P29354
resolver
uniprot
Q14450
resolver
uniprot
Q63057
resolver
uniprot
Q63059
resolver
uniprot_entry
B0LPF3_HUMAN
resolver
uniprot_entry
GRB2_HUMAN
resolver
uniprot_sec
P29354
resolver
uniprot_sec
Q14450
resolver
uniprot_sec
Q63057
resolver
uniprot_sec
Q63059
resolver
amino_acid_sequence
MEAIAKYDFKATADDELSFKRGDILKVLNEECDQNWYKAELNGKDGFIPKNYIEMKPHPWFFGKIPRAKAEEMLSKQRHDGAFLIRESESAPGDFSLSVKFGNDVQHFKVLRDGAGKYFLWVVKFNSLNELVDYHRSTSVSRNQQIFLRDIEQVPQQPTYVQALFDFDPQEDGELGFRRGDFIHVMDNSDPNWWKGACHGQTGMFPRNYVTPVNRNV
uniprot
proteins
function
FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses, including signaling transduction and gene expression (PubMed:11016927, PubMed:11726515, PubMed:37626338). Thus, participates in many biological processes including regulation of innate and adaptive immunity, autophagy, DNA repair or necroptosis (PubMed:35831301, PubMed:37626338, PubMed:38182563). Controls signaling complexes at the T-cell antigen receptor to facilitate the activation, differentiation, and function of T-cells (PubMed:36864087, PubMed:9489702). Mechanistically, engagement of the TCR leads to phosphorylation of the adapter protein LAT, which serves as docking site for GRB2 (PubMed:9489702). In turn, GRB2 establishes a a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation (PubMed:12171928, PubMed:25870599). Functions also a role in B-cell activation by amplifying Ca(2+) mobilization and activation of the ERK MAP kinase pathway upon recruitment to the phosphorylated B-cell antigen receptor (BCR) (PubMed:25413232, PubMed:29523808). Plays a role in switching between autophagy and programmed necrosis upstream of EGFR by interacting with components of necrosomes including RIPK1 and with autophagy regulators SQSTM1 and BECN1 (PubMed:35831301, PubMed:38182563). Regulates miRNA biogenesis by forming a functional ternary complex with AGO2 and DICER1 (PubMed:37328606). Functions in the replication stress response by protecting DNA at stalled replication forks from MRE11-mediated degradation. Mechanistically, inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks (PubMed:38459011). Additionally, directly recruits and later releases MRE11 at DNA damage sites during the homology-directed repair (HDR) process (PubMed:34348893). {ECO:0000269|PubMed:11016927, ECO:0000269|PubMed:11726515, ECO:0000269|PubMed:12171928, ECO:0000269|PubMed:1322798, ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:25413232, ECO:0000269|PubMed:25870599, ECO:0000269|PubMed:29523808, ECO:0000269|PubMed:34348893, ECO:0000269|PubMed:35831301, ECO:0000269|PubMed:36864087, ECO:0000269|PubMed:37328606, ECO:0000269|PubMed:37626338, ECO:0000269|PubMed:38182563, ECO:0000269|PubMed:38459011, ECO:0000269|PubMed:9489702}.; FUNCTION: [Isoform 2]: Does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death. Mechanistically, inhibits RAS-ERK signaling and downstream cell proliferation by competing with GRB2 for SOS1 binding and thus by regulating SOS1 membrane recruitment (PubMed:36171279). {ECO:0000269|PubMed:36171279, ECO:0000269|PubMed:8178156}.
uniprot
proteins
mass_dalton
25206
uniprot
proteins
mutagenesis
MUTAGEN 36; /note="W->F: Loss of binding to AGO2."; /evidence="ECO:0000269|PubMed:37328606"; MUTAGEN 49; /note="P->L: Ineffective in DNA synthesis. Abolishes interaction with SHB; when associated with L-206. Abolishes interaction with SOS1."; /evidence="ECO:0000269|PubMed:1322798, ECO:0000269|PubMed:8493579, ECO:0000269|PubMed:9484780"; MUTAGEN 89; /note="E->K: No effect on the interaction with SOS1."; /evidence="ECO:0000269|PubMed:8493579"; MUTAGEN 90; /note="S->N: No effect on the interaction with SOS1."; /evidence="ECO:0000269|PubMed:8493579"; MUTAGEN 109; /note="K->R: Loss of polyubiquitination."; /evidence="ECO:0000269|PubMed:34348893"; MUTAGEN 123; /note="V->P: Strong loss of clustering of phospho-LAT at the T-cell plasma membrane."; /evidence="ECO:0000269|PubMed:36864087"; MUTAGEN 193; /note="W->F: Loss of binding to AGO2."; /evidence="ECO:0000269|PubMed:37328606"; MUTAGEN 203; /note="G->R: Ineffective in DNA synthesis. Abolishes interaction with SOS1."; /evidence="ECO:0000269|PubMed:1322798, ECO:0000269|PubMed:8493579"; MUTAGEN 206; /note="P->L: Abolishes interaction with SHB; when associated with L-49."; /evidence="ECO:0000269|PubMed:9484780
uniprot
proteins
post_translational_modification
PTM: Phosphorylation of Tyr-209 in the C-terminal SH3 domain reduces its binding to SOS1. {ECO:0000269|PubMed:11726515}.; PTM: Ubiquitinated by RNF173, leading to proteasomal degradation and inhibition of the RAF/MEK/ERK pathway (PubMed:37328606). In the nucleus, polyubiquitinated by RBBP6 at Lys-109 at DNA damage sites (PubMed:34348893). {ECO:0000269|PubMed:34348893, ECO:0000269|PubMed:37328606}.
uniprot
proteins
protein_family
GRB2/sem-5/DRK family
uniprot
proteins
pubmed
10022120
uniprot
proteins
pubmed
10026169
uniprot
proteins
pubmed
10051406
uniprot
proteins
pubmed
10086340
uniprot
proteins
pubmed
10090780
uniprot
proteins
pubmed
10318918
uniprot
proteins
pubmed
10395476
uniprot
proteins
pubmed
10747847
uniprot
proteins
pubmed
10867024
uniprot
proteins
pubmed
10942756
uniprot
proteins
pubmed
10980613
uniprot
proteins
pubmed
11016927
uniprot
proteins
pubmed
11063574
uniprot
proteins
pubmed
11433379
uniprot
proteins
pubmed
11518702
uniprot
proteins
pubmed
11533253
uniprot
proteins
pubmed
11726515
uniprot
proteins
pubmed
11827484
uniprot
proteins
pubmed
11912194
uniprot
proteins
pubmed
12171928
uniprot
proteins
pubmed
12359715
uniprot
proteins
pubmed
12475979
uniprot
proteins
pubmed
12486104
uniprot
proteins
pubmed
12514734
uniprot
proteins
pubmed
12925710
uniprot
proteins
pubmed
1322798
uniprot
proteins
pubmed
1384039
uniprot
proteins
pubmed
15102829
uniprot
proteins
pubmed
15302586
uniprot
proteins
pubmed
15488758
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15526160
uniprot
proteins
pubmed
16129412
uniprot
proteins
pubmed
16582911
uniprot
proteins
pubmed
16625196
uniprot
proteins
pubmed
17081983
uniprot
proteins
pubmed
17974561
uniprot
proteins
pubmed
18296648
uniprot
proteins
pubmed
18559951
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
19109239
uniprot
proteins
pubmed
19509291
uniprot
proteins
pubmed
19523899
uniprot
proteins
pubmed
19608861
uniprot
proteins
pubmed
19690332
uniprot
proteins
pubmed
19815557
uniprot
proteins
pubmed
19836242
uniprot
proteins
pubmed
19914172
uniprot
proteins
pubmed
20521079
uniprot
proteins
pubmed
20933011
uniprot
proteins
pubmed
21179510
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21930792
uniprot
proteins
pubmed
22027826
uniprot
proteins
pubmed
22561606
uniprot
proteins
pubmed
22814378
uniprot
proteins
pubmed
23154388
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23946459
uniprot
proteins
pubmed
24098653
uniprot
proteins
pubmed
25092874
uniprot
proteins
pubmed
25413232
uniprot
proteins
pubmed
25870599
uniprot
proteins
pubmed
25944712
uniprot
proteins
pubmed
27041574
uniprot
proteins
pubmed
29030480
uniprot
proteins
pubmed
29523808
uniprot
proteins
pubmed
30282717
uniprot
proteins
pubmed
31462771
uniprot
proteins
pubmed
32555452
uniprot
proteins
pubmed
34348893
uniprot
proteins
pubmed
35687021
uniprot
proteins
pubmed
35831301
uniprot
proteins
pubmed
36171279
uniprot
proteins
pubmed
36864087
uniprot
proteins
pubmed
37328606
uniprot
proteins
pubmed
37626338
uniprot
proteins
pubmed
38182563
uniprot
proteins
pubmed
38459011
uniprot
proteins
pubmed
7568038
uniprot
proteins
pubmed
7664271
uniprot
proteins
pubmed
7716522
uniprot
proteins
pubmed
7881903
uniprot
proteins
pubmed
8178156
uniprot
proteins
pubmed
8262059
uniprot
proteins
pubmed
8388384
uniprot
proteins
pubmed
8491186
uniprot
proteins
pubmed
8493579
uniprot
proteins
pubmed
8723348
uniprot
proteins
pubmed
8794768
uniprot
proteins
pubmed
8798570
uniprot
proteins
pubmed
9062191
uniprot
proteins
pubmed
9108392
uniprot
proteins
pubmed
9148935
uniprot
proteins
pubmed
9178760
uniprot
proteins
pubmed
9233773
uniprot
proteins
pubmed
9422736
uniprot
proteins
pubmed
9484780
uniprot
proteins
pubmed
9489702
uniprot
proteins
pubmed
9553137
uniprot
proteins
pubmed
9642078
uniprot
proteins
sequence_length
217
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:21179510, ECO:0000269|PubMed:37328606}. Cytoplasm {ECO:0000269|PubMed:21179510, ECO:0000269|PubMed:30282717, ECO:0000269|PubMed:37328606}. Endosome {ECO:0000269|PubMed:21179510}. Golgi apparatus {ECO:0000250|UniProtKB:Q60631}.
uniprot
proteins