Fer is a downstream effector of insulin and mediates the activation of signal transducer and activator of transcription 3 in myogenic cells.
Fer is an intracellular tyrosine kinase that associates with signal transducer and activator of transcription 3 (Stat3) in mammalian cells. However, the signaling pathways in which this interaction plays a functional role have not been revealed. Herein, we show that insulin up-regulates the levels of the fer mRNA and Fer protein in myoblasts that undergo insulin-induced myogenic differentiation. Moreover, insulin directs the interaction of Fer with members of the Janus family of tyrosine kinases (Jak)-Stat3 signaling pathway. Although in untreated cells Fer binds Jak1 and its tyrosine phosphorylation level is low, insulin treatment induced the phosphorylation of Fer and its dissociation from Jak1. The up-regulation of Fer and its dissociation from Jak1 were accompanied by an augmented association of activated Fer with Stat3 and by a concomitant increase in the tyrosine phosphorylation of Stat3. Dissociation of Fer and Jak1, as well as elevation in the level of Fer and in the tyrosine phosphorylation of Stat3, depended on the activity of phosphatidylinositol 3-kinase (PI3K) and was abolished by a PI3K inhibitor. However, Fer and Stat3 were only mildly affected by low concentrations of IGF-I, another activator of the PI3K pathway that can also induce myogenic differentiation. RNA interference directed toward the fer mRNA did not affect the cellular levels of Stat3 but led to a dramatic reduction in the tyrosine phosphorylation level of this transcription factor. Thus, Fer is a downstream effector of insulin and mediates the activation of Stat3 in myogenic cells.
Taler
Michal
M
Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Shpungin
Sally
S
Salem
Yaniv
Y
Malovani
Hana
H
Pasder
Orel
O
Nir
Uri
U
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053613:Janus Kinase 1; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D053613:Janus Kinase 1; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; C494087:Stat3 protein, mouse; C052602:proto-oncogene protein c-fes-fps; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C507905:Jak1 protein, mouse