Disease relevance of GRB14

• Among those of breast cancer origin, GRB14 expression strongly correlated with estrogen receptor positivity, and differential expression was also observed among human prostate cancer cell lines [1].
• Grb14 is an adapter protein that is known to be overexpressed in estrogen receptor positive breast cancers, and in a number of prostate cancer cell lines [2].
• These results suggest that GRB14, GPD1, and GDF8 are weight loss-responsive genes in skeletal muscle and that the observed transcriptional modulation of these would be expected to improve insulin signaling, decrease triglyceride synthesis, and increase muscle mass, respectively, with weight loss [3].

High impact information on GRB14

• Grb14, a member of the Grb7 adaptor protein family, possesses a pleckstrin homology (PH) domain, a C-terminal Src homology-2 (SH2) domain, and an intervening stretch of approximately 45 residues known as the BPS region, which is unique to this adaptor family [4].
• We have determined the crystal structure of the Grb14 BPS region in complex with the tyrosine kinase domain of the insulin receptor [4].
• Together with the crystal structure of the SH2 domain, we present a model for the interaction of Grb14 with the insulin receptor, which indicates how Grb14 functions as a selective protein inhibitor of insulin signaling [4].
• Interestingly, the phosphorylation of Grb14 by PKCzeta increased its inhibitory effect on IR tyrosine kinase activity in vitro [5].
• Importantly, this effect required the recruitment of PKCzeta and the phosphorylation of Grb14, providing in vivo evidences for a regulation of Grb14-inhibitory action by ZIP and PKCzeta [5].

Chemical compound and disease context of GRB14

• In this study, a positive correlation between Grb14 protein expression and ER alpha status in breast cancer cell lines led us to investigate regulation of Grb14 by estradiol and insulin, which synergize in the regulation of breast cancer cell proliferation [6].
• FGF receptor phosphotyrosine 766 is a target for Grb14 to inhibit MDA-MB-231 human breast cancer cell signaling [7].

Biological context of GRB14

• Screening of a human breast epithelial cell cDNA library with the tyrosine-phosphorylated C terminus of the epidermal growth factor receptor identified a novel member of the GRB7 gene family, designated GRB14 [1].
• Assignment of the human GRB14 gene to chromosome 2q22-q24 by fluorescence in situ hybridization [8].
• A GST-Grb14 SH2 domain fusion protein exhibited strong binding to activated platelet-derived growth factor (PDGF) receptors (PDGFRs) in vitro, but association between Grb14 and beta-PDGFRs could not be detected in vivo [1].
• This study supports a role for the tankyrases in cytoplasmic signal transduction pathways and suggests that vesicle trafficking may be involved in the subcellular localization or signaling function of Grb14 [9].
• Furthermore, Grb14 phosphorylation was increased under insulin stimulation, suggesting that the PKCzeta-ZIP-Grb14 complex is involved in insulin signaling [5].

Anatomical context of GRB14

• GRB14 mRNA was expressed at high levels in the liver, kidney, pancreas, testis, ovary, heart, and skeletal muscle [1].
• Upon subcellular fractionation, both Grb14 and tankyrase 2 associate with the low density microsome fraction, and association of these proteins in vivo can be detected by co-immunoprecipitation analysis [9].
• In this model, ZIP potentiated the inhibitory action of Grb14 on insulin-induced oocyte maturation [5].
• GRB14, GPD1, and GDF8 as potential network collaborators in weight loss-induced improvements in insulin action in human skeletal muscle [3].
• Grb10 and Grb14, in particular, have been implicated in the regulation of insulin receptor signalling, whereas Grb7 appears predominantly to be involved in focal adhesion kinase-mediated cell migration [10].

Associations of GRB14 with chemical compounds

• Under serum-free conditions, insulin enhanced Grb14 expression but this effect was repressed by estradiol when both hormones were used in combination [6].
• Grb10 and its close homologues Grb7 and Grb14, belong to a family of adapter proteins characterized by a proline-rich region, a central PH domain, and a carboxyl-terminal Src homology 2 (SH2) domain [11].
• The (1)H, (13)C, and (15)N backbone resonance assignments have been made for the Src homology 2 (SH2) domain of the human molecular adapter protein Grb14 [12].
• Biochemical studies demonstrated that Grb14 binds to activated Ras, which may serve as a timing mechanism for downregulation of insulin signaling [13].

Physical interactions of GRB14

• Interaction of these two proteins is constitutive and mediated by a PDK-1 binding motif on Grb14 [14].
• CONCLUSION: Grb14 binds to the Y766 site of MDA-MB-231-FGFR, competing for PLCy activation, thus inducing an arrest of the signaling transduction cascades [7].

Regulatory relationships of GRB14

• Disruption of this motif by point mutation or deletion of the Grb14 SH2 domain prevents the insulin-triggered membrane translocation of PDK-1 [14].
• This was associated with decreased extracellular signal-regulated kinase (Erk)1/2 activation in insulin-stimulated Grb14-overexpressing cells [6].
• Our work therefore suggests that Grb14 may regulate signalling through the IR by controlling its tyrosine dephosphorylation in a site-specific manner [15].

Other interactions of GRB14

• Identification of a novel human tankyrase through its interaction with the adaptor protein Grb14 [9].
• Deletion analyses implicate the N-terminal 110 amino acids of Grb14 and ankyrin repeats 10-19 of tankyrase 2 in mediating this interaction [9].
• Thus, Grb14 serves as an adaptor protein to recruit PDK-1 to activated insulin receptor, thus promoting Akt phosphorylation and transduction of the insulin signal [14].
• Using a system in which c-Myc induction drives cell cycle progression independently of estradiol, we demonstrated that Grb14 regulation was specific to estradiol treatment [6].
• Mapping studies indicated that ZIP interacted through its ZZ zinc finger domain with the phosphorylated insulin receptor interacting region (PIR) of Grb14 [5].

References