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

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

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

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