The Mechanism Of Hyper-phosphorylation By Constitutive Active P38 Driven Nuclear Export Of Substrates

The p38 signal transduction pathway is an evolutionarily conserved stress response mechanism and plays crucial roles in many physiological and pathological processes.p38 signaling can be differentially activated in different contexts.Under certain conditions,p38 is constitutively activated.Large amount of studies have been done on transient activation of p38.However,the biological consequence of constitutive activation of p38 is largely unknown.Through a cellular screening using a library consisted of 300 transcriptional co-factors,we identified CRTC2 as a bona fide downstream substrate of p38.In this study,we report a hyper-phosphorylation driven nuclear export model governing that constitutive activation of p38 represents a common mechanism not only to regulate the nucleocytoplasmic transport of co-factors,but also to promote transcription factor nuclear export,which cross-talked diverse signal pathways?In the case of CRTC2(TcoF for CREB),we demonstrated that constitutive activation of p38 hyper-phosphorylated CRTC2 to promote its nuclear export,consequently resulting in CRE-mediated transcription shut down,and this nuclear export was independent on CRM 1-mediated nucleocytoplasmic shuttle process.In another case,we find that constitutive activation of p38 hyper-phosphorylated transcription factor,FOS,to drive its nuclear export through CRM1.Collectively,our study uncovered a previously unknown mechanism of inactivation of selected transcription,which is hyper-phosphorylation by constitutive active p38 driven nucleocytoplasmic transport of co-factors or transcription factors,which resuit in negatively regulate downstream gene transcription.