Mechanism of STAT3 activation by insulin-like growth factor I receptor

Recent evidence indicates that STAT proteins can be activated by a variety of receptor and non-receptor protein-tyrosine kinases, Unlike cytokine-indu ced activation of STATs, where JAKs are known to play a pivotal role in pho sphorylating STATs, the mechanism for receptor protein-tyrosine kinase-medi ated activation of STATs remains elusive. In this study, we investigated th e activation of STAT proteins by the insulin-like growth factor I receptor (IGF-IR) in vitro and in vivo and assessed the role of JAKs in the process of activation. We found that STAT3, but not STAT5, was activated in respons e to IGF-I in 293T cells cotransfected with IGF-IR and STAT expression vect ors. Moreover, tyrosine phosphorylation of STATS, JAK1, and JAK2 was increa sed upon IGF-I stimulation of endogenous IGF-IR in 293T cells transfected w ith the respective STAT or JAK expression vector. Supporting the observatio n in 293T cells, endogenous STATS was tyrosine-phosphorylated upon IGF-I st imulation in the muscle cell line C2C12 as well as in various embryonic and adult mouse organs during different stages of development. Dominant-negati ve JAK1 or JAK2 was able to block the IGF-IR-mediated tyrosine phosphorylat ion of STATS in 293T cells. A newly identified family of proteins called SO CS (suppressor of cytokine signaling), including SOCS1, SOCS2, SOCS3 and CI S, was able to inhibit the IGF-I-induced STATS activation as well with vary ing degrees of potency, in which SOCS1 and SOCS3 appeared to have the highe r inhibitory ability. Inhibition of STAT3 activation by SOCS could be overc ome by overexpression of native JAK1 and JAK2. We conclude that IGF-I/IGF-I R is able to mediate activation of STATS in vitro and in vivo and that JAKs are essential for the process of activation.