Function And Mechanism Of DYRK Family Kinases In Regulation Of TGF-β Signaling

TGF-β signaling is an essential component in variety of biological processes including cell proliferation, differentiation, development and immune surveillance, and its dysregulation controls various diseases such as inflammation, cancer and organ fibrosis. Screening the human kinome, we identified that DYRK family kinases, depending on their catalytic abilities, attenuate Smad pathway by driving Smad3 for ubiquitylation. Biochemical assays revealed that Smad3 is directly phosphorylated by DYRKs at Thr179 of linker region, which renders Smad to recruit EDD ubiquitin E3 ligase, through association with substrate recognition component VPRBP. VPRBP-DDB1-EDD (EDVP) complex then ubiquitylates Smad3 to impair its capacity of promoter binding and coactivator recruitment, thus preventing TGF-P signaling activation. As a result, silence the expression of VPRBP or DDB1, or applying of small molecule DYRKs inhibitor, potentiates Smad pathway. We presented evidence that DYRKs induced Smad3 phosphorylation and subsequent recruitment of EDVP E3 complex has a drastic effect on Smad signaling. These findings elucidate the new mode for TGF-β/Smad signaling regulation, and proposed the critical role of DYRK kinases and EDVP E3 complex in TGF-β function.