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, Xiao Yong 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. BaillieMiles D. Houslay, Jeffrey D. Molkentin, Jianping Jin, Chi Wing Chow

Research output: Contribution to journalArticle

15 Scopus citations

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 - Sep 2010

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Zhu, H., Suk, H. Y., Yu, R. Y. L., Brancho, D., Olabisi, O., Yang, T. T. C., Yang, X. Y., Zhang, J., Moussaif, M., Durand, J. L., Jelicks, L. A., Kim, J. Y., Scherer, P. E., Frank, P. G., Lisanti, M. P., Calvert, J. W., Duranski, M. R., Lefer, D. J., Huston, E., ... 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