From the point of view of cell growth, the IGF-IR activated by its ligands has three important functions: (a) it is required for optimal growth both in vivo and in vitro, although some growth occurs even in its absence; (b) it is obligatory for the establishment and maintenance of the transformed phenotype and for tumorigenesis for several types of cells; and (c) it protects cells from apoptosis, both in vivo and in vitro. The IGF-I receptor does seem to occupy a central role in these processes. Whereas an overexpressed IGF-I receptor is mitogenic for IGF-I alone and is fully transforming and protects cells from apoptosis, the same cannot be said for overexpressed EGF and PDGF receptors (205, 206). These two receptors can neither induce growth or transform most cells lacking IGF-I receptors. The reversal of the transformed phenotype and the induction of apoptosis that occur when the levels of IGF-I receptors are artificially decreased also point out the essential role of the receptor in these three processes. An important distinction in this regard is that it is not so much an overexpressed IGF-I receptor that is important in transformation but the lack of it that does not allow the transformed phenotype. This distinction is extremely important if we wish to use the IGF-IR as an approach to therapeutic interventions. Returning to more basic questions, a mutational analysis of the IGF-I receptor has shown that specific domains are involved in its mitogenicity or its ability to facilitate transformation and that these two processes can be separated at the level of the receptor itself. This finding raises a crucial question: Is the transforming activity using a pathway that is separate from the mitogenic signaling pathway? Alternatively, is it simply a question of a quantitative effect? The answer to this question could be a very important contribution to the mechanism of transformation. Little is known about the mechanism(s) by which the IGF-I receptor protects cells from apoptosis; here again, some fundamental questions can be raised. Are there specific domains in the receptor for its antiapoptotic activity? Is this activity tied to mitogenesis and/or transformation? Which elements in the signal transduction pathway are involved in these three different functions of the IGF-I receptor? Although many problems are still unresolved, the last few years have seen a very rapid rise in the importance of the IGF-I receptor in both normal and abnormal growth.(ABSTRACT TRUNCATED AT 400 WORDS)