Fer is an intracellular tyrosine kinase that associates with 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 Jak-Stat3 signaling pathway. While 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 was 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 PI3K and were 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.