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Grb2

Domain

The SH3 domains mediate interaction with RALGPS1 and SHB.

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:7775428). Thus, participates in many biological processes including regulation of innate and adaptive immunity, autophagy, DNA repair or necroptosis. Controls signaling complexes at the T-cell antigen receptor to facilitate the activation, differentiation, and function of T-cells. Mechanistically, engagement of the TCR leads to phosphorylation of the adapter protein LAT, which serves as docking site for GRB2. 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. 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). 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. Regulates miRNA biogenesis by forming a functional ternary complex with AGO2 and DICER1. 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. Additionally, directly recruits and later releases MRE11 at DNA damage sites during the homology-directed repair (HDR) process.

Post-translational modifications

Phosphorylation of Tyr-209 in the C-terminal SH3 domain reduces its binding to SOS1.

Ubiquitinated by RNF173, leading to proteasomal degradation and inhibition of the RAF/MEK/ERK pathway. In the nucleus, polyubiquitinated by RBBP6 at Lys-109 at DNA damage sites.

Sequence Similarities

Belongs to the GRB2/sem-5/DRK family.

Tissue Specificity

Wide tissue distribution.

Cellular localization

Alternative names

Ash, Grb2, Growth factor receptor-bound protein 2, Adapter protein GRB2, Protein Ash, SH2/SH3 adapter GRB2

swissprot:P62994 entrezGene:81504

Other research areas