Identification of the Jak/Stat proteins as novel downstream targets of @entity13388 signaling in muscle: implications in the regulation of XXXX expression.

@entity16404 @entity22943 @entity19 @entity13388 @entity10433 @entity4360 @entity55890 @entity16279 @entity669 @entity934
Eph receptors and their cognate ligands ephrins are important players in axon guidance and neural patterning during development of the nervous system. Much of our knowledge about the signal transduction pathways triggered by Eph receptors has been related to the modulation of actin cytoskeleton, which is fundamental in mediating the cellular responses in growth cone navigation, cell adhesion, and cell migration. In contrast, little was known about whether long term activation of Eph receptor would regulate gene expression. Here we report a novel signaling pathway of @entity13388 , which involves activation of the @entity669 kinase @entity16404 and the transcriptional activator @entity10433 . Transfection of COS7 cells with @entity13388 , but not the kinase-dead mutant, induced @entity669 phosphorylation of @entity16404 , @entity16279 , and @entity10433 . Treatment of cultured C2C12 myotubes with @entity55890 also induced @entity669 phosphorylation of @entity10433 , which was abolished by the @entity16404 inhibitor @entity22943 . Moreover, @entity16404 was co-immunoprecipitated with @entity13388 in muscle, and both proteins were concentrated at the neuromuscular junction (NMJ) of adult muscle. By using microarray analysis, we have identified @entity4360 , the critical enzyme that hydrolyzed the neurotransmitter @entity934 at the NMJ, as a downstream target gene of the Jak/Stat pathway in muscle. More importantly, @entity55890 increased the expression of @entity4360 protein in C2C12 myotubes, which was abolished by @entity22943 . In contrast, @entity55890 reduced the expression of fibronectin mRNA in C2C12 myotubes independently of @entity16404 . Finally, the expression level of @entity4360 in limb muscle of @entity13388 null @entity19 was significantly reduced compared with the wild-type control. Taken together, these results have identified Jak/Stat proteins as the novel downstream targets of @entity13388 signaling. In addition, the present study provides the first demonstration of a potential function of Eph receptors and Jak/Stat proteins at the NMJ.
