IGF-I receptor protection from apoptosis in cells lacking the IRS proteins

The type I insulin-like growth factor receptor (IGF-IR) plays a crucial role in cell growth, transformation and protection from apoptosis. Although the mitogenic function of the IGF-IR may require the activation of insulin receptor substrate-1 (IRS-1) or IRS-2, an overexpressed IGF-IR is able to protect 32D cells, which lack IRS-1 and IRS-2, from apoptosis caused by Interleukin-3 (IL-3) withdrawal. Here, using mutational analysis, the authors identify domains of the IGF-IR necessary to protect from apoptosis without downstream signaling from IRS-1 and IRS-2. A receptor mutant of the tyrosine kinase (TK) domain only partially inhibited antiapoptotic signaling, whereas a mutant displaying constitutive autophosphorylation of the receptor did not show enhanced survival activity. Surprisingly, survival signaling was dependent upon tyrosine 950, the binding site for IRS-1, IRS-2, and Shc proteins. Yet, overexpressed Shc and/or IRS-1 could not replace the IGF-IR survival signal, suggesting the existence of other critical substrates. Finally, the C-terminus may encode a proapoptotic signal, as receptors truncated at C-terminal residues 1229 or 1245 were found to inhibit apoptosis better than the wild type (WT) IGF-IR.