Nuclear Import of Smad: A Dissertation

摘要: Signal transduction by transforming growth factor β (TGF-β) cytokines is mediated an evolutionarily conserved mechanism that depends on the Smad proteins to transduce extracellular stimulus into nucleus. In unstimulated state, Smads spontaneously shuttle across nuclear envelope and distribute throughout cell. Upon TGF-β or bone morphogenetic protein (BMP) stimulation, receptor-activated are phosphorylated, assemble complexes with Smad4, become mostly localized in Such signal-induced translocation of activated essential for TGF-β–dependent gene regulation critical embryonic development homeostasis. The molecular machinery responsible this process, especially how imported as complexes, not entirely clear. Thus, I became interested investigating requirements targeting upon stimulation. Recently, whole-genome RNAi screening offers a complementary cell-based approach functionally identify molecules mediate accumulation response TGF-β. first part dissertation, performed genome-wide screen uncovered importin moleskin (Msk) required import Dpp-activated MAD. Both genetic biochemical studies further confirmed finding. also investigated interactions Msk mammalian orthologues, Importin7 8 validated bona fide cargos Imp7/8. Besides Msk, subset nucleoporins factors Thus second thesis, focused NPC mediates Msk-dependent Most these nucleoporins, including Sec13, Nup75, Nup93 Nup205, were thought be structural without known cargo-specific functions. We, however, demonstrated was specifically used MAD but constitutive containing classic localization signal (cNLS). novel pathway-specific functions Sec13 Nup93. Regulation signaling can achieved only modulating modifying phosphorylation status. Previously we identified kinase, Misshapen (Msn), caused linker MAD, resulting negative Dpp ( Drosophila BMP). third biological relevance Msn kinase wings. over-expression suggest regulator Dpp/MAD pathway vivo . As whole, my findings delineated two import: unique nucleoporins. For time, Nups implicated direct involvement of…