title: PMA induces SnoN proteolysis and CD61 expression through an autocrine mechanism.
abstract: Phorbol-12-myristate-13-acetate, also called PMA, is a small molecule that activates protein kinase C and functions to differentiate hematologic lineage cells. However, the mechanism of PMA-induced cellular differentiation is not fully understood. We found that PMA triggers global enhancement of protein ubiquitination in K562, a myelogenous leukemia cell line and one of the enhanced-ubiquitination targets is SnoN, an inhibitor of the Smad signaling pathway. Our data indicated that PMA stimulated the production of Activin A, a cytokine of the TGF-β family. Activin A then activated the phosphorylation of both Smad2 and Smad3. In consequence, SnoN is ubiquitinated by the APC(Cdh1) ubiquitin ligase with the help of phosphorylated Smad2. Furthermore, we found that SnoN proteolysis is important for the expression of CD61, a marker of megakaryocyte. These results indicate that protein ubiquitination promotes megakaryopoiesis via degrading SnoN, an inhibitor of CD61 expression, strengths the roles of ubiquitination in cellular differentiation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical School, United States.
authors.forename: Chonghua
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical School, United States; Program of Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, United States.
authors.forename: Natoya
authors.initials: N
authors.lastname: Peart
authors.affiliation: Department of Molecular and Cellular Biology, The University of Texas at Dallas, Dallas, TX, United States.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Xuan
authors.affiliation: Department of Internal Medicine, Medical School, United States.
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Lewis
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical School, United States; Program of Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical School, United States; Program of Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, United States. Electronic address: Jianping.jin@uth.tmc.edu.
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
mesh_terms: D030201:Activin Receptors, Type I / Q000096:biosynthesis / Q000235:genetics; D030301:Activin Receptors, Type II / Q000096:biosynthesis / Q000235:genetics; D028341:Activins / Q000096:biosynthesis; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D039661:Integrin beta3 / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000096:biosynthesis; D059748:Proteolysis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D034061:Thrombopoiesis / Q000187:drug effects*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D002273:Carcinogens; C061248:ITGB3 protein, human; D039661:Integrin beta3; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C060615:SKIL protein, human; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D025801:Ubiquitin; C422405:activin A; D028341:Activins; D044767:Ubiquitin-Protein Ligases; D011493:Protein Kinase C; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A; D013755:Tetradecanoylphorbol Acetate
keywords: Activin A; Cdh1; Differentiation; Smad2; SnoN; Ubiquitin