Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D

Hong Zhu, Hee Yun Suk, Raymond Y L Yu, Deborah Brancho, Opeyemi Olabisi, Teddy T C Yang, XiaoYong Yang, Jialin Zhang, Mustapha Moussaif, Jorge L. Durand, Linda A. Jelicks, Ja Young Kim, Philipp E. Scherer, Philippe G. Frank, Michael P. Lisanti, John W. Calvert, Mark R. Duranski, David J. Lefer, Elaine Huston, George S. Baillie & 4 others Miles D. Houslay, Jeffrey D. Molkentin, Jianping Jin, Chi Wing Chow

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 E3 ubiquitin ligase complex upon dual phosphorylation by casein kinase 1 (CK1) and glycogen synthase kinase 3β (GSK3β) 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/GSK3β 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.

Original languageEnglish (US)
Pages (from-to)4379-4390
Number of pages12
JournalMolecular and Cellular Biology
Volume30
Issue number18
DOIs
StatePublished - 2010

Fingerprint

Type 4 Cyclic Nucleotide Phosphodiesterase
Calcineurin
Tacrolimus
Casein Kinase I
Cyclic AMP
Cyclosporine
Glycogen Synthase Kinase 3
Immunosuppressive Agents
5'-Nucleotidase
Ubiquitin-Protein Ligases
Caenorhabditis elegans
Ubiquitin
GTP-Binding Proteins
Phosphoric Monoester Hydrolases
Protein Kinases
Motivation
Signal Transduction
Transplantation
Phosphorylation
Transplants

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Medicine(all)

Cite this

Zhu, H., Suk, H. Y., Yu, R. Y. L., Brancho, D., Olabisi, O., Yang, T. T. C., ... Chow, C. W. (2010). Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D. Molecular and Cellular Biology, 30(18), 4379-4390. https://doi.org/10.1128/MCB.01193-09

Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D. / Zhu, Hong; Suk, Hee Yun; Yu, Raymond Y L; Brancho, Deborah; Olabisi, Opeyemi; Yang, Teddy T C; Yang, XiaoYong; Zhang, Jialin; Moussaif, Mustapha; Durand, Jorge L.; Jelicks, Linda A.; Kim, Ja Young; Scherer, Philipp E.; Frank, Philippe G.; Lisanti, Michael P.; Calvert, John W.; Duranski, Mark R.; Lefer, David J.; Huston, Elaine; Baillie, George S.; Houslay, Miles D.; Molkentin, Jeffrey D.; Jin, Jianping; Chow, Chi Wing.

In: Molecular and Cellular Biology, Vol. 30, No. 18, 2010, p. 4379-4390.

Research output: Contribution to journalArticle

Zhu, H, Suk, HY, Yu, RYL, Brancho, D, Olabisi, O, Yang, TTC, Yang, X, Zhang, J, Moussaif, M, Durand, JL, Jelicks, LA, Kim, JY, Scherer, PE, Frank, PG, Lisanti, MP, Calvert, JW, Duranski, MR, Lefer, DJ, Huston, E, Baillie, GS, Houslay, MD, Molkentin, JD, Jin, J & Chow, CW 2010, 'Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D', Molecular and Cellular Biology, vol. 30, no. 18, pp. 4379-4390. https://doi.org/10.1128/MCB.01193-09
Zhu, Hong ; Suk, Hee Yun ; Yu, Raymond Y L ; Brancho, Deborah ; Olabisi, Opeyemi ; Yang, Teddy T C ; Yang, XiaoYong ; Zhang, Jialin ; Moussaif, Mustapha ; Durand, Jorge L. ; Jelicks, Linda A. ; Kim, Ja Young ; Scherer, Philipp E. ; Frank, Philippe G. ; Lisanti, Michael P. ; Calvert, John W. ; Duranski, Mark R. ; Lefer, David J. ; Huston, Elaine ; Baillie, George S. ; Houslay, Miles D. ; Molkentin, Jeffrey D. ; Jin, Jianping ; Chow, Chi Wing. / Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D. In: Molecular and Cellular Biology. 2010 ; Vol. 30, No. 18. pp. 4379-4390.
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