Insulin, insulin-like growth factor-1, and platelet-derived growth factor activate extracellular signal-regulated kinase by distinct pathways in muscle cells

We have investigated the signaling pathways initiated by insulin, insulin-l ike growth factor-1 (IGF-I), and platelet-derived growth factor (PDGF) lead ing to activation of the extracellular signal-regulated kinase (ERK) in L6 myotubes. Insulin but not IGF-I or PDGF-induced ERK activation was abrogate d by Ras inhibition, either by treatment with the farnesyl. transferase inh ibitor FTP III, or by actin disassembly by cytochalasin D, previously shown to inhibit Ras activation. The protein kinase C (PKC) inhibitor bisindolym aleimide abolished PDGF but not IGF-I or insulin-induced ERR activation. ER K activation by insulin, IGF-I, or PDGF was unaffected by the phosphatidyli nositol 3-kinase inhibitor wortmannin but was abolished by the MEK inhibito r PD98059. In contrast, activation of the pathway involving phosphatidylino sitol 3-kinase (PI3k), protein kinase B, and glycogen synthase kinase 3 (GS K3) was mediated similarly by all three receptors, through a PI 3-kinase-de pendent but Ras- and actin-independent pathway. We conclude that ERK activa tion is mediated by distinct pathways including: (i) a cytoskeleton- and Ra s-dependent, PKC-independent, pathway utilized by insulin, (ii) a PKC-depen dent, cytoskeleton- and Ras-independent pathway used by PDGF, and (iii) a c ytoskeleton-, Ras-, and PKC-independent pathway utilized by IGF-I. (C) 2001 Academic Press.