IGF-II Mediates Mitogenic Signaling in IGF-I-Resistant Efe Pygmy T-Cell Lines• 424

Abstract

The growth-promoting actions of IGF-II are generally believed to be mediated through the type type 1 IGF (IGF-I) receptor, while IGF-II signaling through its own receptor regulates translocation of mannose-6-phosphated (M6P) proteins to lysosomes for degradation. We previously reported IGF-I resistance and markedly decreased expression and function of type 1 IGF receptors in T-cell lines established from African Efe Pygmies. We have now examined IGF-II signaling in these IGF-I-resistant Pygmy T-cells. The 260-kDa IGF-II/M6P receptor was normally expressed in Pygmy T-cells. There were comparable numbers of IGF-II binding sites per cell [9271 ± 1830 vs. 12,646± 5396 (p=NS)] and affinities [816 ± 75 vs. 1027 ± 283 pM(p=NS)] between Pygmy and control T-cells, respectively. IGF-II induced intracellular protein tyrosine phosphorylation, and functioned biologically to stimulate equivalent colony formation of Pygmy and control T-cell lines [peak stimulation 158 ± 17% vs. 140 ± 18%, respectively, at 9 ng/mL of IGF-II (p=NS)]. These results indicate that: (1) Efe Pygmy T-cells have intact IGF-II receptor expression and binding; (2) IGF-II signaling without type 1 IGF receptor activation is associated with tyrosine kinase activity and phosphorylation of intracellular proteins; and (3) a functional type 1 IGF receptor is not required for IGF-II-induced proliferation of Efe Pygmy T-cells. We speculate that IGF-II signaling may partially compensate for decreased expression and function of type 1 IGF receptors in Efe Pygmies.