GRB2

Official Full Name

growth factor receptor bound protein 2

Organism

Homo sapiens

GeneID

2885

Background

The protein encoded by this gene binds the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. This gene is similar to the Sem5 gene of C.elegans, which is involved in the signal transduction pathway. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Synonyms

ASH; Grb3-3; MST084; NCKAP2; MSTP084; EGFRBP-GRB2;

Bio Chemical Class

mRNA target

Protein Sequence

MEAIAKYDFKATADDELSFKRGDILKVLNEECDQNWYKAELNGKDGFIPKNYIEMKPHPWFFGKIPRAKAEEMLSKQRHDGAFLIRESESAPGDFSLSVKFGNDVQHFKVLRDGAGKYFLWVVKFNSLNELVDYHRSTSVSRNQQIFLRDIEQVPQQPTYVQALFDFDPQEDGELGFRRGDFIHVMDNSDPNWWKGACHGQTGMFPRNYVTPVNRNV

Open

Disease

Acute myeloid leukaemia, Malignant haematopoietic neoplasm, Mature B-cell lymphoma, Myelodysplastic syndrome, Myeloproliferative neoplasm

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The adaptor protein growth factor receptor-bound protein 2 (Grb2) is a broadly expressed adaptor protein, which activates Ras and MAP kinases in growth factor receptor signaling. Grb2 consists of one central SH2 domain which is flanked by two SH3 domains. Therefore, Grb2 is a classical adaptor protein with no catalytic protein domains.

Grb2 and Receptor Tyrosine Kinase (RTK) Signaling

Grb2, initially discovered as the missing link between the epidermal growth factor receptor (EGFR) and the Ras-mitogen-activated protein kinase (MAPK) pathway, is required for signaling by nearly all RTKs. Grb2 uses its N-terminal SH3 domain to associate constitutively with the guanine nucleotide exchange factor (GEF) Son of Sevenless (Sos) and becomes recruited to phosphorylated RTKs via its SH2 domain. This event translocates Sos to the vicinity of its substrate, Ras, allowing Sos to catalyze the exchange of guanine diphosphate (GDP) to guanine triphosphate (GTP). GTP hydrolysis by Ras then initiates activation of kinase Raf and the downstream kinase cascade. FGFRs lack the canonical Grb2 SH2 domain–binding motif and thus are incapable of recruiting the Grb2-Sos complex directly to the activated receptor. Instead, FGFRs phosphorylate FRS2α and β, which are myristoylated membrane-anchored docking proteins, and these phosphorylated proteins act as the platform for the recruitment of the Grb2-Sos complex to the receptor complex. Apart from translocating Sos to the membrane, Grb2 also positively regulates FGFR signaling through binding to the phosphatase Shp2, which then dephosphorylates Sprouty proteins, key intracellular inhibitors of FGF signaling. Finally, Grb2 associates with Gab1, another adaptor protein, which participates in the phosphoinositide 3-kinase (PI3K)–Akt pathway.

Figure 1. Distinct pools of Grb2 relay the signal from the activated receptors to different proteins and secondary messengers.

Grb2-mediated dimerization of the cytoplasmic domains of RTK could influence the organization of the receptor ectodomain, potentially affecting ligand binding. In fact, a study by McKeehan et al. suggested that the intracellular orientation of the cytoplasmic domains in FGFR2 affects binding of FGF7 ligands to receptor ectodomain. Grb2-mediated regulation of FGFR basal phosphorylation provides a new opportunity for the design of a novel class of modulators of FGF signaling. Specific inhibitors of dimeric Grb2 binding to FGFR could be used to promote FGF signaling in tissue repair and wound healing, whereas agents that augment Grb2-FGFR binding could find use for inhibition of FGFR signaling in FGFR-driven cancers.

Grb2 and B-cell Receptor (BCR) Signaling

In B cell lines, it was shown that Grb2 can inhibit BCR-induced Ca²⁺ signaling. Ackermann et al. generated a B-cell-specific Grb2-deficient mouse line, which had a severe reduction of mature follicular B cells in the periphery due to a differentiation block and decreased B-cell survival. Furthermore, they also found several changes in important signaling pathways: enhanced BCR-induced Ca²⁺ signaling, alterations in mitogen-activated protein kinase activation patterns and strongly impaired Akt activation, the latter pointing towards a defect in PI3K signaling. Interestingly, B-cell-specific Grb2-deficient mice showed impaired IgG and B-cell memory responses, and impaired germinal centre formation. Therefore, Grb2-dependent signaling pathways are important for lymphocyte differentiation processes, as well as for control of secondary humoral immune responses. The crucial role of Grb2 in humoral immune responses suggests that this well-known adaptor protein may offer a completely new potential as a target for therapies.

References:

Ackermann J A, et al. Grb2 regulates B-cell maturation, B-cell memory responses and inhibits B-cell Ca²⁺ signalling. Embo Journal, 2014, 30(8):1621-1633.
Jang I K, et al. Growth-factor receptor-bound protein-2 (Grb2) signaling in B cells controls lymphoid follicle organization and germinal center reaction. Proceedings of the National Academy of Sciences, 2011, 108(19):7926-7931.
Lin C C, et al. Inhibition of Basal FGF Receptor Signaling by Dimeric Grb2. Cell, 2012, 149(7).
Belov A A, Mohammadi M. Grb2, a Double-Edged Sword of Receptor Tyrosine Kinase Signaling. Science Signaling, 2012, 5(249):pe49-pe49.

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