title: Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D.
abstract: Calcineurin is a widely expressed and highly conserved Ser/Thr phosphatase. Calcineurin is inhibited by the immunosuppressant drug cyclosporine A (CsA) or tacrolimus (FK506). The critical role of CsA/FK506 as an immunosuppressant following transplantation surgery provides a strong incentive to understand the phosphatase calcineurin. Here we uncover a novel regulatory pathway for cyclic AMP (cAMP) signaling by the phosphatase calcineurin which is also evolutionarily conserved in Caenorhabditis elegans. We found that calcineurin binds directly to and inhibits the proteosomal degradation of cAMP-hydrolyzing phosphodiesterase 4D (PDE4D). We show that ubiquitin conjugation and proteosomal degradation of PDE4D are controlled by a cullin 1-containing E(3) ubiquitin ligase complex upon dual phosphorylation by casein kinase 1 (CK1) and glycogen synthase kinase 3beta (GSK3beta) in a phosphodegron motif. Our findings identify a novel signaling process governing G-protein-coupled cAMP signal transduction-opposing actions of the phosphatase calcineurin and the CK1/GSK3beta protein kinases on the phosphodegron-dependent degradation of PDE4D. This novel signaling system also provides unique functional insights into the complications elicited by CsA in transplant patients.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Hee Yun
authors.initials: HY
authors.lastname: Suk
authors.forename: Raymond Y L
authors.initials: RY
authors.lastname: Yu
authors.forename: Deborah
authors.initials: D
authors.lastname: Brancho
authors.forename: Opeyemi
authors.initials: O
authors.lastname: Olabisi
authors.forename: Teddy T C
authors.initials: TT
authors.lastname: Yang
authors.forename: XiaoYong
authors.initials: X
authors.lastname: Yang
authors.forename: Jialin
authors.initials: J
authors.lastname: Zhang
authors.forename: Mustapha
authors.initials: M
authors.lastname: Moussaif
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Durand
authors.forename: Linda A
authors.initials: LA
authors.lastname: Jelicks
authors.forename: Ja-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.forename: Mark R
authors.initials: MR
authors.lastname: Duranski
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.forename: Elaine
authors.initials: E
authors.lastname: Huston
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Chow
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D019143:Evolution, Molecular; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D025801:Ubiquitin; D016572:Cyclosporine; D000242:Cyclic AMP; D019703:Calcineurin; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D046988:Proteasome Endopeptidase Complex