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

Biochem Biophys Res Commun. 2001 Oct 19;288(1):205-11. doi: 10.1006/bbrc.2001.5762.

Abstract

We have investigated the signaling pathways initiated by insulin, insulin-like growth factor-1 (IGF-I), and platelet-derived growth factor (PDGF) leading to activation of the extracellular signal-regulated kinase (ERK) in L6 myotubes. Insulin but not IGF-I or PDGF-induced ERK activation was abrogated by Ras inhibition, either by treatment with the farnesyl transferase inhibitor FTP III, or by actin disassembly by cytochalasin D, previously shown to inhibit Ras activation. The protein kinase C (PKC) inhibitor bisindolylmaleimide abolished PDGF but not IGF-I or insulin-induced ERK activation. ERK activation by insulin, IGF-I, or PDGF was unaffected by the phosphatidylinositol 3-kinase inhibitor wortmannin but was abolished by the MEK inhibitor PD98059. In contrast, activation of the pathway involving phosphatidylinositol 3-kinase (PI3k), protein kinase B, and glycogen synthase kinase 3 (GSK3) was mediated similarly by all three receptors, through a PI 3-kinase-dependent but Ras- and actin-independent pathway. We conclude that ERK activation is mediated by distinct pathways including: (i) a cytoskeleton- and Ras-dependent, PKC-independent, pathway utilized by insulin, (ii) a PKC-dependent, cytoskeleton- and Ras-independent pathway used by PDGF, and (iii) a cytoskeleton-, Ras-, and PKC-independent pathway utilized by IGF-I.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Line
  • Cytoskeleton / metabolism
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Insulin / pharmacology*
  • Insulin-Like Growth Factor I / pharmacology*
  • MAP Kinase Signaling System*
  • Mitogen-Activated Protein Kinase Kinases / physiology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / enzymology*
  • Organophosphonates / pharmacology
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphorylation
  • Platelet-Derived Growth Factor / pharmacology*
  • Protein Kinase C / physiology
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
  • Proto-Oncogene Proteins p21(ras) / metabolism

Substances

  • 2-(2-oxo-2-((3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy)aminoethyl)phosphonic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester sodium
  • Actins
  • Enzyme Inhibitors
  • Insulin
  • Organophosphonates
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins
  • Insulin-Like Growth Factor I
  • Glycogen Synthase Kinases
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Glycogen Synthase Kinase 3
  • Mitogen-Activated Protein Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)