Both ARMS along with the RTKs are diffusely distributed about the sarcolemma of muscle in newborn rats. With the progres sion of development, the proteins turn into even more concentrated in the NMJ. Colocalization of ARMS and EphA4/TrkB clusters is evident at postsynaptic junctional online websites in adult muscle. Along with the biochemical selleck inhibitor evidence exhibiting the interac tion between ARMS and RTKs, these observations strongly propose that the expression of ARMS is temporally and spatially coregulated with Eph and Trk receptors while in muscle improvement. As an evolutionally conserved substrate for Trk and Eph receptors, ARMS may play an essential function in modulating ephrin/neu rotrophin signaling on the NMJ. ARMS enhances Eph receptor signaling by expanding EphA4 induced Jak and Stat phosphorylation What might be the functions of ARMS in the NMJ We previ ously reported that the activation of EphA4 induces the ty rosine phosphorylation of Jak and Stat, which are two novel downstream effectors within the Eph receptor signal transduction pathway.
From the presence of ARMS, we ob served a significant enhance in the EphA4 induced tyrosine phosphorylation of Jak kinases and Stat1 proteins. On the other hand, the tyrosine phosphorylation of EphA4 in differentiated C2C12 myotubes was lowered once the expression of ARMS and syntrophin was impaired. ARMS syntro phin may possibly regulate the oligomerization of EphA4 in response to ephrin A1, which is important for signal transduction down stream PCI-24781 CRA-02478 of the RTK. Alternatively, because ARMS contains various protein protein interaction domains and syntrophin is known as a well known scaffold protein, these proteins could perform as docking online websites for the downstream ef fectors of EphA4 by recruiting them to the signaling complex while in Eph activated signal transduction.
This hypothesis is constant together with the current findings that

ARMS interacts with and recruits CrkL to the Trk receptor while in sustained MAPK activation. Due to its proximity to EphA4 and TrkB at the producing NMJ, ARMS, together with syntrophin, could coordinate the molecular events that are es sential for synapse growth. For the reason that ARMS itself can also be tyrosine phosphorylated following the activation of Eph and Trk re ceptors, it will eventually be fascinating to find out regardless of whether the phos phorylation of ARMS is needed for its regulation of ephrin and neurotrophin signaling. Syntrophins interact with ARMS and regulate ARMS localization ARMS contains a consensus PDZ domain binding motif on its COOH terminus that’s predicted to have a high affinity for class I PDZ domains. Implementing yeast two hybrid and biochemical stud ies, we identified and 2 syntrophins as interacting partners, whereas one syntrophin interacted only with ARMS COOH ter minus in yeast but not with complete length ARMS in mammalian cells.