Human growth factor receptor bound 14 binds the activated insulin receptor and alters the insulin-stimulated tyrosine phosphorylation levels of multiple proteins

Hemming, Richard; Agatep, Ronald; Badiani, Ketan; Wyant, Kerrie; Arthur, Gilbert; Gietz, R. Daniel; Triggs-Raine, Barbara L.

doi:10.1139/o00-090

Cited by 28 publications

(25 citation statements)

References 34 publications

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“…Grb14 binds activated IR (30) and inhibits the phosphorylation of IR substrates (6). Overexpression of Grb14 has been shown to inhibit the activation of downstream insulin signaling cascades (6,26,30). Consistent with the role of Grb14 as an inhibitor of IR signaling, Grb14 Ϫ/Ϫ mice display improved glucose tolerance, increased insulin sensitivity, and enhanced insulin signaling (14).…”

Section: Discussionmentioning

confidence: 78%

Tankyrase 2 Poly(ADP-Ribose) Polymerase Domain-Deleted Mice Exhibit Growth Defects but Have Normal Telomere Length and Capping

Hsiao

Poitras

Cook

et al. 2006

Molecular and Cellular Biology

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Regulation of telomere length maintenance and capping are a critical cell functions in both normal and tumor cells. Tankyrase 2 (Tnks2) is a poly(ADP-ribose) polymerase (PARP) that has been shown to modify itself and TRF1, a telomere-binding protein. We show here by overexpression studies that tankyrase 2, like its closely related homolog tankyrase 1, can function as a positive regulator of telomere length in human cells, dependent on its catalytic PARP activity. To study the role of Tnks2 in vivo, we generated mice with the Tnks2 PARP domain deleted. These mice are viable and fertile but display a growth retardation phenotype. Telomere analysis by quantitative fluorescence in situ hybridization (FISH), flow-FISH, and restriction fragment analysis showed no change in telomere length or telomere capping in these mice. To determine the requirement for Tnks2 in long-term maintenance of telomeres, we generated embryonic stem cells with the Tnks2 PARP domain deleted and observed no change, even upon prolonged growth, in telomere length or telomere capping. Together, these results suggest that Tnks2 has a role in normal growth and development but is not essential for telomere length maintenance or telomere capping in mice.

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Section: Discussionmentioning

confidence: 78%

Tankyrase 2 Poly(ADP-Ribose) Polymerase Domain-Deleted Mice Exhibit Growth Defects but Have Normal Telomere Length and Capping

Hsiao

Poitras

Cook

et al. 2006

Molecular and Cellular Biology

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“…Grb14 is selectively expressed in insulin-sensitive tissues and upon insulin stimulation interacts in vivo with the insulin receptor (IR). Moreover, the overexpression of Grb14 in the CHO-IR cell line was shown to inhibit insulin-stimulated tyrosine phosphorylation of specific proteins, like IRS-1, and distal effects, like DNA and glycogen synthesis (23,28). Despite controversial findings (46,52,71), overexpression studies of Grb10 isoforms are also consistent with a negative role in insulin signaling (34,44,48).…”

mentioning

confidence: 95%

The Adapter Protein ZIP Binds Grb14 and Regulates Its Inhibitory Action on Insulin Signaling by Recruiting Protein Kinase Cζ

Cariou¹,

Perdereau²,

Cailliau

et al. 2002

Molecular and Cellular Biology

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Grb14 is a member of the Grb7 family of adapters and acts as a negative regulator of insulin-mediated signaling. Here we found that the protein kinase C (PKC) interacting protein, ZIP, interacted with Grb14. Coimmunoprecipitation experiments demonstrated that ZIP bound to both Grb14 and PKC, thereby acting as a link in the assembly of a PKC-ZIP-Grb14 heterotrimeric complex. Mapping studies indicated that ZIP interacted through its ZZ zinc finger domain with the phosphorylated insulin receptor interacting region (PIR) of Grb14. PKC phosphorylated Grb14 under in vitro conditions and in CHO-IR cells as demonstrated by in vivo labeling experiments. Furthermore, Grb14 phosphorylation was increased under insulin stimulation, suggesting that the PKC-ZIP-Grb14 complex is involved in insulin signaling. The PIR of Grb14, which also interacts with the catalytic domain of the insulin receptor (IR) and inhibits its activity, was preferentially phosphorylated by PKC. Interestingly, the phosphorylation of Grb14 by PKC increased its inhibitory effect on IR tyrosine kinase activity in vitro. The role of ZIP and Grb14 in insulin signaling was further investigated in vivo in Xenopus laevis oocytes. In this model, ZIP potentiated the inhibitory action of Grb14 on insulininduced oocyte maturation. Importantly, this effect required the recruitment of PKC and the phosphorylation of Grb14, providing in vivo evidences for a regulation of Grb14-inhibitory action by ZIP and PKC. Together, these results suggest that Grb14, ZIP, and PKC participate in a new feedback pathway of insulin signaling.

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“…Overexpression of Grb14 in CHO-IR cells inhibits insulinstimulated DNA and glycogen synthesis or tyrosine phosphorylation of proteins [8,9]. In vitro tyrosine kinase assays have shown that the Grb7 family members inhibit the IR catalytic activity, and that Grb14 is the most potent inhibitor [10,11].…”

Section: Introductionmentioning

confidence: 99%

The PIR domain of Grb14 is an intrinsically unstructured protein: implication in insulin signaling

et al. 2003

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Grb14 belongs to the Grb7 family of adapter proteins and was identi¢ed as a negative regulator of insulin signal transduction. Its inhibitory e¡ect on the insulin receptor kinase activity is controlled by a newly discovered domain called PIR. To investigate the biochemical and biophysical characteristics of this new domain, we cloned and puri¢ed recombinant PIR-SH2, PIR, and SH2 domains. The isolated PIR and PIR-SH2 domains were physiologically active and inhibited insulin-induced reinitiation of meiosis in the Xenopus oocytes system. However, NMR experiments on 15 N-labelled PIR revealed that it did not present secondary structure. These results suggest that the PIR domain belongs to the growing family of intrinsically unstructured proteins. ß

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Human growth factor receptor bound 14 binds the activated insulin receptor and alters the insulin-stimulated tyrosine phosphorylation levels of multiple proteins

Cited by 28 publications

References 34 publications

Tankyrase 2 Poly(ADP-Ribose) Polymerase Domain-Deleted Mice Exhibit Growth Defects but Have Normal Telomere Length and Capping

Tankyrase 2 Poly(ADP-Ribose) Polymerase Domain-Deleted Mice Exhibit Growth Defects but Have Normal Telomere Length and Capping

The Adapter Protein ZIP Binds Grb14 and Regulates Its Inhibitory Action on Insulin Signaling by Recruiting Protein Kinase Cζ

The PIR domain of Grb14 is an intrinsically unstructured protein: implication in insulin signaling

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