Insulin-like growth factor I receptor activated by a transmembrane mutation.

We constructed mutant receptors by mutating transmembrane Val922 of the human insulin-like growth factor I receptor (IGF-IR). Assays of receptor kinase and autophosphorylation revealed constitutively augmented tyrosine kinase activity of V922E IGF-IR in both transient and stable expression. The constitutively active tyrosine kinase of this mutant was verified by promoted tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in the absence of IGF-I. In CHO cells stably increasing V922E IGF-IR, both IRS-1 phosphorylation and the IRS-1 associated phosphoinositide 3-kinase activity were stimulated in the absence of IGF-I to the level attained by 1 nM IGF-I stimulation of wild-type IGF-IR, whereas the Ras-mitogen-activated protein kinase pathway was not activated under the same condition. In these CHO cells, V922E IGF-IR significantly stimulated glucose uptake but did not promote mitogenesis in the absence of IGF-I. We thus conclude that the V922E mutation of IGF-IR switches on the intrinsic tyrosine kinase and differentially activates the downstream pathways. This mutant is extremely useful in clarifying the turning-on mechanism of IGF-IR as well as the differential roles of individual downstream pathways of receptor tyrosine kinases.