Different Effects on Mitogenesis and Transformation of a Mutation at Tyrosine 1251 of the Insulin-like Growth Factor I Receptor

Abstract

The wild type insulin-like growth factor I (IGF-I) receptor has both mitogenic and transforming activities. We have examined the effect of point mutations at tyrosine residues 1250 and 1251 on these two properties of the receptor. For this purpose, we stably transfected plasmids expressing mutant and wild type receptors into R ؊ cells, which are 3T3-like cells, derived from mouse embryos with a targeted disruption of the IGF-I receptor genes, and therefore devoid of endogenous IGF-I receptors. A tyrosine to phenylalanine mutation of either the 1250 or 1251 residue, or both, has no effect on the ability of the receptor to transmit a mitogenic signal. However, the tyrosine 1251 mutant receptor and the double mutant have lost the ability to transform R ؊ cells (colony formation in soft agar), even when the receptors are expressed at very high levels, while the Y1250F mutant is fully transforming. These experiments show that the 1251 tyrosine residue is required for the transforming activity of the IGF-I receptor.

Requirement for Phosphatidylinositol 3-Kinase in Epidermal Growth Factor-Induced AP-1 Transactivation and Transformation in JB6 P+ Cells

“…Cell transformation is a complex process which is different from cell mitogenesis and involves a wide array of signaling events, such as the MAP kinase signal cascade and other signal pathway (7,20,28,29,41,50,51). In some cases, cell transformation is dissociated from mitogenesis (7,20,41).…”

“…It is well known that epidermal growth factor (EGF) can induce a high level of AP-1 activity and cell transformation as well as PI 3-kinase activity. Cell transformation is a complex process and much different from cell mitogenesis; in some cases, these two events are dissociated (7,20,29,41,51). Currently, little is known regarding whether PI 3-kinase and its products are involved in EGF-induced signal transduction to the transcriptional machinery of the nucleus and cell transformation.…”

The contradictions of the insulin-like growth factor 1 receptor

“…This ®nding has since been con®rmed with di erent viral and cellular oncogenes and in di erent laboratories. The list of agents that fail to transform Rcells include the SV40 T antigen and/or an activated Ha-ras oncogene (Sell et al, 1993, the bovine papilloma virus E5 protein , the human papilloma virus E7 protein (Steller et al, 1996), the Ewing sarcoma fusion protein (Toretsky et al, 1997), an activated c-src , an over-expressed IRS-1 (D'Ambrosio et al, 1995) and over-expressed growth factor receptors, such as the EGF , PDGF (DeAngelis et al, 1995) and insulin (Miura et al, 1995) receptors. All these agents readily transform MEF with endogenous IGF-IR.…”

Impaired Shc, Ras, and MAPK Activation but Normal Akt Activation in FL5.12 Cells Expressing an Insulin-like Growth Factor I Receptor Mutated at Tyrosines 1250 and 1251

“…A double tyrosine to phenylalanine mutant Y1250F/Y1251F displays a very dramatic phenotype, in that cells expressing this mutant are completely deficient in suppression of apoptosis by IGF-I in response to IL-3 withdrawal, serum deprivation, or activation of c-Myc (6). The Y1250F/Y1251F mutant receptor is competent for mitogenic activity, but is also deficient in anchorage-independent growth (21), and cells expressing it have altered cytoskeletal organization (22) as well as decreased metastatic potential and synthesis of matrix metalloproteinases (20). However, the mechanism by which mutation of these two tyrosines results in specific abrogation of IGF-IR function has not been elucidated.…”