Functional And Mechanistic Studies Of WDR74 In TGF-? Signaling Pathway

Transforming growth factor-?(TGF-?)superfamily signaling controls numerous cellular responses in all metazoans.They regulate cell proliferation,differentiation,extracellular matrix remodeling and embryonic development.In the canonical TGF-? signaling pathway,TGF-? signaling are transduced by transmembrane serine/threonine kinase receptors and intracellular effectors Smads.Upon activation,R-Smad(Smad2 and Smad3)are phosphorylated at their C termini SSXS motifs by TGF-? type I receptor.The phosphorylated R-Smads form a complex with co-Smad(Smad4)and then accumulated in the nucleus where the Smads complex regulates transcription through DNA binding and transcriptional factors association.Smads cooperate with many transcriptional coactivators(p300/CBP)or corepressors(Ski)to mediate their transcription activity.Therefore,signal transduction requires Smads interactions with multiple intracellular proteins.WDR74 belongs to the superfamily of WD40 repeat proteins which contains six WD domains and is an evolutionarily conserved protein.WDR74 was first identified up-regulation in lung metastasis canine mammary gland cells compared with primary tumor cells.This suggested that WDR74 may be essential for metastatic potential of cancer cells.WDR74 was also found to be required for mouse blastocyst formation.Recently,some evidence suggested that WDR74 is a novel regulatory protein,involved in ribosome biogenesis.Although it is well-documented that the superfamily of WD40 repeat proteins regulate many cellular functions,such as cell division,cell-fate determination,gene transcription,transmembrane signaling,mRNA modification,and vesicle fusion,however,very little is known about WDR74.In this study,we identified that WDR74 is a new Smad-binding protein and functionally promotes TGF-? signaling.WDR74 significantly enhances TGF-?-induced transcriptional responses,thus facilitates TGF-?-induced cell growth arrest,EMT and cell migration.