Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction

Oncogene. 1997 Nov 20;15(21):2529-39. doi: 10.1038/sj.onc.1201429.

Abstract

The binding of insulin to its receptor initiates multiple signal transduction pathways regulating such diverse processes as proliferation, differentiation, glucose transport, and glycogen metabolism. The STAT-family of transcription factors has been demonstrated to play a critical role in gene induction by a variety of hemopoietic cytokines and hormones. Furthermore, constitutive activation of STATs is observed in transformed cells. Here we describe activation of a transcriptional complex binding to a consensus STAT-transcriptional element in response to insulin challenge. This complex is induced rapidly after tyrosine autophosphorylation of the insulin receptor, and is sustained for several hours. Supershift analysis of the insulin-induced complex reveals that it specifically contains the transcription factor Stat3. DAN binding of this complex is inhibited by pre-incubation with tyrosine, but not serine/threonine protein kinase inhibitors, whereas transcriptional activation is inhibited by both. Utilising a dominant negative mutant of p21ras we demonstrate that both insulin-induced Stat3 DNA-binding and also transactivation do not require p21ras. Furthermore, although previous studies have suggested a role for MAP kinases (ERKs) and PI-3K in STAT activation, utilising the specific MEK inhibitor PD098059 and the PI-3K inhibitor wortmannin, we demonstrate that activation of ERKs or PI-3K are not required for insulin induced Stat3 phosphorylation or transactivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • Cells, Cultured
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Insulin / pharmacology*
  • Mice
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Phosphatidylinositol 3-Kinases / physiology*
  • Proto-Oncogene Proteins p21(ras) / physiology
  • STAT3 Transcription Factor
  • Signal Transduction / drug effects*
  • Trans-Activators / metabolism*
  • Transcriptional Activation

Substances

  • DNA-Binding Proteins
  • Insulin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • DNA
  • Phosphatidylinositol 3-Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Proto-Oncogene Proteins p21(ras)