Regulation of survival signals from the insulin-like growth factor-I receptor

Suppression of apoptosis by survival factors is important for the maintenan ce of normal tissue homoeostasis and the response to infection or injury. S urvival factors such as insulin-like growth factor-I (IGF-I) initiate a sig nalling cascade that starts by tyrosine phosphorylation of substrates leadi ng to the activation of serine kinases that modulate the activity of member s of the Bcl-2 family, which regulates the apoptotic machinery in most cell s. Tumour cells often have enhanced survival mechanisms due either to up-re gulation of the IGF-I receptor and its ligands or to loss of function of a phosphatase (PTEN) that regulates part of this survival pathway. The C-term inus of the IGF-I receptor appears to be a regulatory domain for the anti-a poptotic activity of this receptor, and certain residues within the C-termi nus are essential for this regulatory activity. Knowledge of the proteins a nd pathways, which interact with these C-terminal domains, should lead us t o ways of modulating IGF-I-mediated survival in tumours.