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.
Dews
M
M
Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Nishimoto
I
I
Baserga
R
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006412:Hematopoietic Stem Cells; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010750:Phosphoproteins / Q000172:deficiency / Q000502:physiology*; D017354:Point Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D014162:Transfection
D055504:Insulin Receptor Substrate Proteins; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin