Variation among cell types in the signaling pathways by which IGF-I stimulates specific cellular responses.

This review compares the signaling pathways leading to cellular responses (primarily proliferation and differentiation) of cells to the insulin-like growth factors (IGFs). Although some systems (such as myoblasts and adipocytes) clearly employ the Ras-Raf-Mitogen Activated Protein (MAP) kinase pathway in signaling for cell proliferation, others (such as MCF-7 mammary tumors and brain capillary cells) proliferate in response to signals mediated by phosphatidylinositol-3 kinase and p70 S6 kinase. Similarly, most of the systems surveyed use a phosphatidylinositol-3 kinase pathway in differentiating in response to IGFs, but others (such as SH-SY5Y neuroblastoma cells) differentiate in response to the MAP kinase pathway.

Raf-1 activation stimulates proliferation and inhibits IGF-stimulated differentiation in L6A1 myoblasts.

Our previous work has demonstrated that the insulin-like growth factors (IGFs), acting through a single receptor, stimulate both proliferation and differentiation of L6A1 myoblasts. This unique model system has enabled us to closely examine the switch that regulates these two opposing responses. We have previously shown, using specific inhibitors of the IGF-I signal transduction pathway, that the mitogenic response is mediated by the Ras/Raf/MAP kinase pathway and the myogenic response by the PI 3-kinase/p70s6k pathway (Coolican SA, Samuel DS, Ewton DZ, McWade FJ, Florini JR, J Biol Chem 1997; 272: 6653-62).

Modulation of insulin-like growth factor actions in L6A1 myoblasts by insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5: a dual role for IGFBP-5.

We have previously shown that the insulin-like growth factors (IGFs) stimulate both proliferation and differentiation of skeletal muscle cells in culture, and that these actions in L6A1 muscle cells may be modulated by three secreted IGF binding proteins (IGFBPs), IGFBP-4, -5, and -6. Since we found that the temporal expression pattern of IGFBP-4 and IGFBP-5 differed dramatically during the transition from proliferating myoblasts to differentiated myotubes, we undertook the current study to examine the effects of purified IGFBP-4 and IGFBP-5 on IGF-stimulated actions in L6A1 muscle cells. As has been shown for other cell types, we found that IGFBP-4 had only inhibitory actions, inhibiting IGF-I and IGF-II-stimulated proliferation and differentiation.

The mitogenic and myogenic actions of insulin-like growth factors utilize distinct signaling pathways.

It is well established that mitogens inhibit differentiation of skeletal muscle cells, but the insulin-like growth factors (IGFs), acting through a single receptor, stimulate both proliferation and differentiation of myoblasts. Although the IGF-I mitogenic signaling pathway has been extensively studied in other cell types, little is known about the signaling pathway leading to differentiation in skeletal muscle. By using specific inhibitors of the IGF signal transduction pathway, we have begun to define the signaling intermediates mediating the two responses to IGFs.

Growth hormone and the insulin-like growth factor system in myogenesis.

It is very clear that the GH-IGF axis plays a major role in controlling the growth and differentiation of skeletal muscles, as it does virtually all of the tissues in the animal body. One aspect of this control is unquestioned: circulating GH acts on the liver to stimulate expression of the IGF-I and IGFBP3 genes, substantially increasing the levels of these proteins in the circulation. It also seems that GH stimulates expression of IGF-I genes in skeletal muscle, although there are a number of cases in which skeletal muscle IGF-I expression is elevated in the absence of GH.