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Papers In Press, published online ahead of print July 9, 2001
Surgery Medicine and Oncology, McGill University Health Center, Montreal, Quebec H3A 1A1
Corresponding Author: pnina.brodt{at}muhc.mcgill.ca
The receptor for the type 1 insulin like growth factor (IGF-I) regulates multiple cellular functions impacting on the metastatic phenotype of tumor cells including cellular proliferation, anchorage -independent growth, survival, migration, synthesis of the 72 kDa type IV collagenase and invasion. We have used site-directed mutagenesis to generate domain-specific mutants of the receptor b subunit in order to analyze the role of specific tyrosines in the regulation of the invasive/metastatic phenotype. Poorly invasive M-27 carcinoma cells expressing low receptor numbers were transfected with a plasmid vector expressing IGF-I receptor cDNA in which single or multiple tyrosine codons in the kinase domain namely Y1131, Y1135 and Y1136 or the C-terminal tyrosines 1250,1251 were substituted with phenylalanine. Changes in the invasive/metastatic properties were analyzed relative to M-27 cells expressing wild type receptor. We found that cells expressing the Y1131,1135,1136F or Y1135F receptor mutants lost all IGF-IR-dependent functions and their phenotypes were indistinguishable from, or suppressed relative to the parent line. The Y1250,1251F substitution abolished anchorage-independent growth, cell spreading and the anti apoptotic effect of IGF-I while all other IGF-IR dependent phenotypes were either unperturbed (i.e. mitogenicity) or only partially reduced (migration and invasion). The results identify 3 types of receptor–dependent functions in this model: those dependent only on an intact kinase domain (DNA synthesis), those dependent equally on kinase domain and Y1250/1251-signaling (e.g. apoptosis, soft agar cloning) and those dependent on kinase domain and enhanced through Y1250/1251- signaling (migration, invasion). They suggest that signals derived from both regions of the receptor cooperate to enhance tumor metastasis.
J. Biol. Chem, 10.1074/jbc.M102754200
Submitted on March 28, 2001
Revised on June 11, 2001
Accepted on July 6, 2001
Cooperative regulation of the invasive/metastatic phenotype by different domains of the type I insulin like growth factor receptor beta subunit
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