Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14

Depetris, Rafael S.; Wu, Jiangxue; Hubbard, Stevan R.

doi:10.1038/nsmb.1642

Cited by 64 publications

(117 citation statements)

References 40 publications

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“…However, most previous GRB10 studies have been conducted in immortalised cell lines in vitro and it is not clear what role GRB10 plays in modulating insulin sensitivity in vivo. Moreover, a recent study using crystallography demonstrated that GRB10 binds to the insulin receptor far too weakly to have any significant physiological effect on insulin action [18]. These results raise questions about the proposed role of the GRB10 protein in the development of skeletal muscle insulin resistance, at least via any effect on insulin receptor phosphorylation [16,17].…”

Section: Introductionmentioning

confidence: 46%

Lentivirus shRNA Grb10 targeting the pancreas induces apoptosis and improved glucose tolerance due to decreased plasma glucagon levels

Doiron

Norton

et al. 2012

Diabetologia

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Aims/hypothesis The physiological significance of growth factor receptor-bound protein-10 (GRB10) in the pancreas is unclear. We hypothesised that GRB10 is involved in pancreatic apoptosis, as GRB10 binds with a family of cell-survivalrelated proteins implicated in apoptosis. Methods Lentiviral vector small hairpin RNA (shRNA) targeting Grb10 was injected in vivo via an intraductal pancreatic route to target pancreatic tissues in adult mice, which were studied 2 weeks post-injection. Results Using the TUNEL assay, we demonstrated for the first time that in vivo injection of lentivirus shRNA Grb10 directly into the adult mouse pancreas induced apoptosis in both exocrine and endocrine (alpha and beta) cells. This effect was more pronounced in alpha cells. Levels of the pro-apoptotic protein BCL2-interacting mediator of cell death (BIM) in islets was higher in lentivirus shRNA Grb10 than in lentivirus shRNA scramble mice. In the apoptotic pathway, BIM initiates apoptosis signalling, leading to activation of the caspase cascade. We propose that, when complexed with GRB10, BIM is inactive. On activation by stress signalling or, in the present study, following injection of lentivirus shRNA Grb10 into pancreas, BIM becomes unbound from GRB10 and activates the caspase cascade. Indeed, caspase-3 activity in islets was higher in the experimental than in the control group. Apoptosis induced by shRNA Grb10 resulted in a 34% decrease in fasting plasma glucagon. Mice injected with shRNA Grb10 had improved glucose tolerance despite reduced insulin secretion compared with shRNA scramble control mice. Conclusions/interpretation GRB10 is critically involved in alpha cell survival and, as a result, plays an important role in regulating basal glucagon secretion and glucose tolerance in adult mice.

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Section: Introductionmentioning

confidence: 46%

Lentivirus shRNA Grb10 targeting the pancreas induces apoptosis and improved glucose tolerance due to decreased plasma glucagon levels

Doiron

Norton

et al. 2012

Diabetologia

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“…The BPS domain interacts with the 14-3-3 protein, another protein scaffold with numerous protein partners, and BCL2L11, a proapoptotic scaffold protein required for normal immune function (18,19). The PH domain has the fewest interacting partners although it has been confirmed to bind phosphoinositides (PIs), critical components of the cell membrane that affect vesicle transport and cell signaling (20). This interaction is consistent with the requirement of the PH domain for Grb10 localization to the cell membrane.…”

Section: Grb10 Binding Partners Define Its Role In Developmentmentioning

confidence: 52%

“…The RA domain of Grb7 and Grb14 extensively interacts with Ras-GTPases, important regulators of intercellular signaling related to cell growth and vesicle transport (21). Grb10 has been confirmed to bind at least one of these GTPases, NRAS (20). Finally, the PR domain binds to GIGYF1/2, proteins that are implicated in the modulation of insulin signaling and neuronal survival but have currently unclear molecular functions (22).…”

Section: Grb10 Binding Partners Define Its Role In Developmentmentioning

confidence: 99%

Tissue-specific regulation and function of Grb10 during growth and neuronal commitment

Plasschaert

Bartolomei

2014

Proc. Natl. Acad. Sci. U.S.A.

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Growth-factor receptor bound protein 10 (Grb10) is a signal adapter protein encoded by an imprinted gene that has roles in growth control, cellular proliferation, and insulin signaling. Additionally, Grb10 is critical for the normal behavior of the adult mouse. These functions are paralleled by Grb10’s unique tissue-specific imprinted expression; the paternal copy of Grb10 is expressed in a subset of neurons whereas the maternal copy is expressed in most other adult tissues in the mouse. The mechanism that underlies this switch between maternal and paternal expression is still unclear, as is the role for paternally expressed Grb10 in neurons. Here, we review recent work and present complementary data that contribute to the understanding of Grb10 gene regulation and function, with specific emphasis on growth and neuronal development. Additionally, we show that in vitro differentiation of mouse embryonic stem cells into alpha motor neurons recapitulates the switch from maternal to paternal expression observed during neuronal development in vivo. We postulate that this switch in allele-specific expression is related to the functional role of Grb10 in motor neurons and other neuronal tissues.

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“…The gene product is an adapter protein that binds to insulin and insulin-like growth factor receptors inhibiting tyrosine kinase signaling. 39,40 GRB14 − / − mice are lean and have improved insulin sensitivity. The rs3923113 risk allele is associated with reduced insulin sensitivity and T2D in South Asians, indicating a gain of function.…”

Section: Discussionmentioning

confidence: 99%

Effect of six type II diabetes susceptibility loci and an FTO variant on obesity in Pakistani subjects

Shabana

Shahid

et al. 2015

Eur J Hum Genet

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The aim of the current study was to analyze the effect of six type II diabetes GWAS loci rs3923113 (GRB14), rs16861329 (ST6GAL1), rs1802295 (VPS26A), rs7178572 (HMG20A), rs2028299 (AP3S2) and rs4812829 (HNF4A), and an FTO polymorphism (rs9939609) on obesity. The probable mechanism of action of these SNPs was analyzed by studying their association with various biochemical and anthropometric parameters. A total of 475 subjects (obese = 250, controls = 225) were genotyped by TaqMan assay and their lipid profile was determined. Allele/genotype frequencies and an unweighted/weighted gene score were calculated. The effect of the gene score on anthropometric and biochemical parameters was analyzed. The minor allele frequencies of all variants were comparable to that reported in the original studies and were associated with obesity in these Pakistani subjects. Subjects with 9 risk alleles differ from those with o3 and overall there is no significant effect (P-value for trend 0.26). None of the SNPs were associated with any of the serum lipid traits. We are the first to report the association of these T2D SNPs with obesity. In the Pakistani population the reported effect of six SNPs for obesity is similar to that reported for T2D and having a combination of risk alleles on obesity can be considerable. The mechanism of this effect is unclear, but appears not to be mediated by changing serum lipid chemistry.

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Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14

Cited by 64 publications

References 40 publications

Lentivirus shRNA Grb10 targeting the pancreas induces apoptosis and improved glucose tolerance due to decreased plasma glucagon levels

Lentivirus shRNA Grb10 targeting the pancreas induces apoptosis and improved glucose tolerance due to decreased plasma glucagon levels

Tissue-specific regulation and function of Grb10 during growth and neuronal commitment

Effect of six type II diabetes susceptibility loci and an FTO variant on obesity in Pakistani subjects

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