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Professor of Microbiology and Immunology Kimmel Cancer Center Thomas Jefferson University Philadelphia, Pennsylvania 19107
Address all correspondence and requests for reprints to: Renato Baserga, M.D., Professor of Microbiology and Immunology, Thomas Jefferson University, Kimmel Cancer Center, 624 Bluemle Life Sciences Building, Philadelphia, Pennsylvania 19107.
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PDGF, EGF, and the IGFs activate the corresponding tyrosine kinase receptors, from which originates a signaling pathway that is common to the three growth factors, although the IGFs (like insulin) use docking proteins (for instance, IRS-1 and IRS-2), which are not needed by the PDGF and EGF receptors. This pathway is very well known. It involves many transducing molecules (PI 3 kinase, Grb2, Sos, Raf, ras, the MAP kinases cascade, p92, all the way to the nucleus) and has been analyzed in several reviews (1, 2, 3). For convenience, I will call it the ras pathway.
Although it is quite clear that the ras pathway is one of the mitogenic pathways for these three receptors, it cannot be the only one, at least as far as the IGF-I receptor is concerned. Mouse embryo fibroblasts with a targeted disruption of the IGF-I receptor genes, R-cells, can grow in 10% serum but cannot grow in serum-free medium supplemented by a variety of growth factors (4, 5), even when the receptors for PDGF and EGF are overexpressed (reviewed in 6 . Furthermore, R-cells stably transfected with an activated ras are still incapable of growing in defined medium supplemented by growth factors (5). The behavior of R-cells tells us that the IGF-I receptor has an additional mitogenic pathway that is not the ras pathway and that is not shared with the PDGF and EGF receptors. There are other reports indicating the existence of a mitogenic, ras-independent pathway, as most recently shown by the elegant experiments of Barone and Courtneidge (7).
Lowe et al. (in this issue) come up with a similar conclusion. They used human breast cancer cells, whose growth can be inhibited by cAMP. Their results are clear: 1) both IGF-I and EGF stimulate ERK1 and ERK2 activities, and their stimulation is not inhibited by an increase in intracellular cAMP; 2) both IGF-I and EGF increase transcription from a serum-responsive element (SRE), but, this time, an increase in cAMP intracellular concentration does inhibit the stimulation by either IGF-I or EGF. The unavoidable conclusion is that cAMP inhibits the growth of human breast cancer cells by a mechanism that is ERK-independent: by extrapolation, a ras-independent pathway.
A brief digression: Lowe et al. have measured growth by an indirect method, i.e. by measuring the amount of protein. In this, they are like almost everybody else in the field of endocrine growth factors, although most investigators use radioactive thymidine incorporation, as a measure of what they call (somewhat loosely) a mitogenic response. Neither of these methods are an accurate or even reliable indication of cell proliferation. There is only one way of measuring the mitogenicity of a growth factor, and that is to count the number of cells before and after. Reviewers, though, will have to be taught that an increase in cells in DNA synthesis, from 1% to 95%, will result in only a doubling in cell number.
Is the pathway suggested by the experiments of Lowe et al. the same as the one suggested by the experiments of Sell et al. (5)? I do not think so, and the reason is that the experiments of Sell et al. (5, 6) indicate a ras-independent pathway that is not shared with the PDGF and EGF receptors. In the case of Lowe et al., their pathway is common to IGF-I and EGF. This additional pathway originating exclusively from the IGF-I receptor (it is absent in the insulin receptor) is probably a pathway that plays a major role in the establishment and maintenance of the transformed phenotype (reviewed in 8 .
Unfortunately, I do not have the slightest idea of what is this elusive pathway, and the literature says that I am in good company. It is not for lack of trying: since we discovered, a few years ago, that a new, ras-independent pathway was involved in the mitogenic and transforming activities of the IGF-I receptor, we explored many avenues, from peptide binding to the yeast two hybrid system, so far unsuccessfully. The only thing we know is that this pathway is not required for protection from apoptosis (9).
How can this hypothetical pathway be reconciled with the findings of Lowe et al. ? Well, the poet Robert Frost had only to chose between two roads that diverged in the wood (... and I, I took the one less traveled by), but a cell obviously has many more choices. They could be totally different pathways, whose existence so far can only be postulated, or they could be pathways branching off from the original ras pathway. They may originate from a substrate that interacts directly with the IGF-I receptor, or from a substrate that interacts with the docking proteins. Perhaps signaling from the IGF-I receptor is modulated by other signaling systems, such as G proteins, or protein kinase C, or the JAK/Stat transducing pathway, all of which are already known to cross-talk with IRS-1, for instance.
At any rate, the take-home lesson is that, although the ras pathway is certainly important in mitogenesis and transformation, it is perhaps time that we also invest our time and intellects in elucidating the paths that are less traveled by. As the breast cancer cells studied by Lowe et al. suggest, it may lead to some practical applications.
Received March 31, 1997.
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