Mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways are not sufficient for insulin-like growth factor I-induced mitogenesis and tumorigenesis

Endocrinology
A G ScrimgeourD LeRoith

Abstract

Insulin-like growth factor-I (IGF-I) and insulin are known to activate a signaling cascade involving ras --> kappa raf-1 --> mitogen-activated protein (MAP) kinase kinase (MEK) --> p42/p44 MAP kinase (Erk-1 and -2). Recent reports suggest that activation of this ras/MAP kinase pathway is involved in mitogenesis and c-fos transcription but is not required for insulin action on metabolic processes such as glycogen synthesis, lipogenesis, and GLUT-4-mediated glucose transport. Previously we and others have demonstrated that substitution of both tyrosines at positions 1250 and 1251 in the carboxy-terminal region of the human IGF-I receptor has relatively small effects on receptor and endogenous substrate phosphorylation but completely abrogated the ability of these cells to form tumors in nude mice or proliferate in response to IGF-I in culture. Replacement of the tyrosine at position 1316 also did not affect the kinase activity of the receptor with respect to autophosphorylation or phosphorylation of endogenous substrates but did reduce the ability of the receptor to mediate mitogenic or tumorigenic signals. To further characterize the role of these tyrosines in IGF-I receptor function, we have used three distinct approaches to ex...Continue Reading

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Citations

Aug 21, 2001·Biochemical and Biophysical Research Communications·B HimmelmannP Nissley
Dec 20, 2012·Journal of Biomolecular Structure & Dynamics·I-Chi HungCalvin Yu-Chian Chen
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