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Activation of the phosphatidyl inositol 3-kinase (PI 3-kinase) is one of the immediate events in signaling by the insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF-IR). The IR and IGF-IR are two closely related tyrosine kinases, which are activated on binding of their respective ligands. Previous studies have proposed that the two receptors interact directly with the SH2 domains of the Mr 85K regulatory subunit (p85) of PI 3- kinase via phosphorylated Y1322THM and Y1316AHM sequences located in the carboxyl-terminal domain of the IR and the IGF-IR, respectively. We In this study we have used the yeast two-hybrid system to compare the interaction of the cytoplasmic domains of the IR and the IGF-IR with p85. We found that the IR is more efficient in interacting with the p85 than is the IGF-IR. For both receptors, deletion of the region containing the Y1322THM sequence in the IR and the Y1316AHM-similar sequence in the IGF-IR decreases their ability to interact with p85. However, these mutated receptors still interacted with the full-length p85, suggesting that other regions in the receptors might be involved in the interaction. Furthermore, mutations of the three major autophosphorylation sites indicate that interactions with p85 are dependent on the receptor tyrosine kinase activity. Finally, we asked whether the two SH2 domains of p85 (n-SH2 and c-SH2) are involved in the same fashion in their association with the two receptors. Interestingly, we observed that the carboxyl- terminal domain of the IGF-IR associates only with the p85 c-SH2 domain, whereas the corresponding domain of the IR interacts with both the n-SH2 and the c-SH2 domains. In combination, both SH2 domains (n/c-SH2) contribute to the maximal interaction observed with the full-length p85. Although the precise impact on signaling resulting from these differences in the interaction of p85 with the IR vs. the IGF-IR remains to be determined, it is tempting to propose that they contribute, at least in part, to the specificity of the biological responses induced by insulin vs. IGF-1.

endocrinology

Interaction of the molecular weight 85K regulatory subunit of the phosphatidylinositol 3-kinase with the insulin receptor and the insulin-like growth factor-1 (IGF- I) receptor: comparative study using the yeast two-hybrid system.