Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2

Kasus‐Jacobi, Anne; Béréziat, Véronique; Perdereau, Dominique; Girard, Jean; Burnol, Anne-Françoise

doi:10.1038/sj.onc.1203469

Cited by 45 publications

(50 citation statements)

References 35 publications

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“…However, remarkably for all three Grbs the inhibitory effect on IR catalytic activity is mediated by the PIR, in agreement with a recent paper reporting an in vitro inhibitory effect of the BPS domain of Grb10 on the IR catalytic activity (45). It has been shown that the PIR and SH2 domains of the various Grb proteins are differentially implicated in the interaction with the IR (6). The SH2 domain is responsible for the binding of Grb7 to the IR, whereas both PIR and SH2 are equally important in the Grb10-IR interaction, and the PIR is the main binding domain in the IR-Grb14 interaction.…”

Section: Discussionsupporting

confidence: 76%

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Inhibition of Insulin Receptor Catalytic Activity by the Molecular Adapter Grb14

Béréziat¹,

Kasus‐Jacobi²,

Perdereau

et al. 2002

Journal of Biological Chemistry

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146

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Grb14 belongs to the Grb7 family of adapters and was recently identified as a partner of the insulin receptor (IR).Here we show that Grb14 inhibits in vitro IR substrate phosphorylation. Grb14 does not alter the K m for ATP and behaves as an uncompetitive inhibitor for the IR substrate. Similar experiments performed with other members of the Grb7 family, Grb7 and Grb10, and with IGF-1 receptor argue in favor of a specific inhibition of the IR catalytic activity by Grb14. The IR-interacting domain of Grb14, the PIR, is sufficient for the inhibitory effect of Grb14, whereas the SH2 domain has no effect on IR catalytic activity. In Chinese hamster ovary (CHO) cells overexpressing both IR and Grb14, Grb14 binds to the IR as early as 1 min after insulin stimulation, and the two proteins remain associated. When interacting with Grb14, the IR is protected against tyrosine phosphatases action and therefore maintained under a phosphorylated state. However, the binding of Grb14 to the IR induces an early delay in the activation of Akt and ERK1/2 in CHO-IR cells, and ERK1/2 are less efficiently phosphorylated. These findings show that Grb14 is a direct inhibitor of the IR catalytic activity and could be considered as a modulator of insulin signaling.

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Section: Discussionsupporting

confidence: 76%

“…Production of the GST Fusion Proteins-The GST-Grb14 (Grb14, PIR, SH2), GST-Grb7 (Grb7, PIR, SH2), and GST-Shc constructs were described previously (5,6). The mouse GST-Grb10␣ was a gift from J. Finidori.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Insulin Receptor Catalytic Activity by the Molecular Adapter Grb14

Béréziat¹,

Kasus‐Jacobi²,

Perdereau

et al. 2002

Journal of Biological Chemistry

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146

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“…Grb7 has both an SH2 and a PTB domain (58), each capable of binding to motifs containing a phosphorylated tyrosine (Fig. 8A).…”

Section: Coupling Of Caveolin-1 To the C-src Tyrosine Kinasementioning

confidence: 99%

Palmitoylation of Caveolin-1 at a Single Site (Cys-156) Controls Its Coupling to the c-Src Tyrosine Kinase

Lee¹,

Woodman²,

Engelman³

et al. 2001

Journal of Biological Chemistry

103

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Caveolin-1 was initially identified as a phosphoprotein in Rous sarcoma virus-transformed cells. Previous studies have shown that caveolin-1 is phosphorylated on tyrosine 14 by c-Src and that lipid modification of c-Src is required for this phosphorylation event to occur in vivo.Phosphocaveolin-1 (Tyr(P)-14) localizes within caveolae near focal adhesions and, through its interaction with Grb7, augments anchorage-independent growth and epidermal growth factor-stimulated cell migration. However, the cellular factors that govern the coupling of caveolin-1 to the c-Src tyrosine kinase remain largely unknown. Here, we show that palmitoylation of caveolin-1 at a single site (Cys-156) is required for coupling caveolin-1 to the c-Src tyrosine kinase. Furthermore, upon evaluating a battery of nonreceptor and receptor tyrosine kinases, we demonstrate that the tyrosine phosphorylation of caveolin-1 by c-Src is a highly selective event. We show that Src-induced tyrosine phosphorylation of caveolin-1 can be inhibited or uncoupled by targeting dually acylated proteins (namely carcinoembryonic antigen (CEA), CD36, and the NH 2 -terminal domain of G␣ i1 ) to the exoplasmic, transmembrane, and cytoplasmic regions of the caveolae membrane, respectively. Conversely, when these proteins are not properly targeted or lipid-modified, the ability of c-Src to phosphorylate caveolin-1 remains unaffected. In addition, when purified caveolae preparations are preincubated with a myristoylated peptide derived from the extreme N terminus of c-Src, the tyrosine phosphorylation of caveolin-1 is abrogated; the same peptide lacking myristoylation has no inhibitory activity. However, an analogous myristoylated peptide derived from c-Yes also has no inhibitory activity. Thus, the inhibitory effects of the myristoylated c-Src peptide are both myristoylation-dependent and sequence-specific. Finally, we investigated whether phosphocaveolin-1 (Tyr(P)-14) interacts with the Src homology 2 and/or phosphotyrosine binding domains of Grb7, the only characterized downstream mediator of its function. Taken together, our data identify a series of novel lipid-lipid-based interactions as important regulatory factors for coupling caveolin-1 to the c-Src tyrosine kinase in vivo.Dispersed within the "sea" of phospholipids that constitute the plasma membrane are cholesterol/sphingolipid-enriched microdomains called caveolae (1-4). Caveolin proteins are the principal structural components of caveolae membranes (5-8).There are now three known caveolin genes (Cav-1, Cav-2, and Cav-3) that correspond to four different subtypes of caveolin proteins. Caveolin-1 (␣ and ␤) and caveolin-2 proteins have nearly identical tissue distributions, being most abundantly expressed in terminally differentiated cell types (adipocytes, endothelial cells, fibroblasts, type I pneumocytes, and smooth muscle) (9 -14). The caveolin-3 protein, however, is mainly expressed in muscle tissues (15)(16)(17). Several independent lines of evidence now indicate that the expression of either caveolin-...

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“…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]. For all three Grbs, the inhibitory action on the IR kinase activity is mediated by a new interaction domain located between the SH2 and PH domains called either BPS (between PH and SH2) [12] or PIR (phosphorylated insulin receptor interacting region) [8,13]. PIR speci¢cally binds to the regulatory kinase loop of the IR.…”

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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Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2

Cited by 45 publications

References 35 publications

Inhibition of Insulin Receptor Catalytic Activity by the Molecular Adapter Grb14

Inhibition of Insulin Receptor Catalytic Activity by the Molecular Adapter Grb14

Palmitoylation of Caveolin-1 at a Single Site (Cys-156) Controls Its Coupling to the c-Src Tyrosine Kinase

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

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