title: Dissociation of mitogenesis and transforming activity by C-terminal truncation of the insulin-like growth factor-I receptor.
abstract: We have investigated the mitogenic and transforming ability of an IGF-I receptor with a 108-amino-acid C-terminal truncation in R- cells, which are 3T3-like cells derived from mouse embryos in which the IGF-I receptor genes have been disrupted by targeted homologous recombination. R- cells stably transfected with expression plasmids encoding either a wild-type or a truncated human IGF-I receptor were capable of growing in serum-free medium supplemented solely with IGF-I. This response was observed over a wide range of receptor levels. R- cells overexpressing the wild-type IGF-I receptor also formed colonies in soft agar, and colony formation was augmented by coexpression of the SV40 large T antigen. However, all the examined clones of R- cells expressing the truncated IGF-I receptor exhibited a dramatically impaired ability to grow in soft agar, even in the presence of the T antigen. The inability to form colonies in soft agar was not due to a quantitative impairment of signal transduction, because: (1) SV40-transformed cells with a physiological level of the wild-type IGF-I receptor did not respond to IGF-I with cell proliferation, but grew in soft agar; (2) R- cells stably transfected with both a truncated receptor and T antigen, on the contrary, responded with mitogenesis to IGF-I but could not form colonies in soft agar; (3) some clones with the truncated receptor expressed levels of receptor roughly 100-fold the level of wild-type cells; and (4) several parameters of IGF-I receptor signal transduction were not impaired in cells stably transfected with a truncated receptor. Furthermore, overexpression of an activated ras in cells with the truncated IGF-IR did not restore their ability to proliferate under anchorage-independent conditions. We conclude that the 108 amino acids of the IGF-I receptor are not essential for a mitogenic response to IGF-I, but are required for transformation (as assessed by the ability to grow in soft agar), indicating that these two functions can be dissociated at an intramolecular level. Moreover, although ras (activated) certainly plays a role in transformation, the transforming activity of the IGF-IR also requires signaling elements that are ras-dependent.
authors.affiliation: Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: E
authors.initials: E
authors.lastname: Surmacz
authors.forename: C
authors.initials: C
authors.lastname: Sell
authors.forename: J
authors.initials: J
authors.lastname: Swantek
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: C T
authors.initials: CT
authors.lastname: Roberts
authors.forename: D
authors.initials: D
authors.lastname: LeRoith
authors.forename: R
authors.initials: R
authors.lastname: Baserga
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D016895:Culture Media, Serum-Free; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D013539:Simian virus 40 / Q000235:genetics; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D016895:Culture Media, Serum-Free; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017526:Receptor, IGF Type 1; D018631:ras Proteins