Mitogen-activated Protein Kinase Regulation of the Phosphodiesterase RegA in Early Development

Overview

Journal Microbiology (Reading)

Specialty Microbiology

Date 2019 Nov 16

PMID 31730032

Citations 4

Authors

Nirakar Adhikari

Nick A Kuburich

Jeffrey A Hadwiger

Affiliations

Soon will be listed here.

Abstract

Mitogen-activated protein kinase (MAPK) regulation of cAMP-specific phosphodiesterase function has been demonstrated in mammalian cells and suspected to occur in other eukaryotes. Epistasis analysis in the soil amoeba suggests the atypical MAPK Erk2 downregulates the function of the cAMP-specific phosphodiesterase RegA to regulate progression of the developmental life cycle. A putative MAPK docking motif located near a predicted MAPK phosphorylation site was characterized for contributions to RegA function and binding to Erk2 because a similar docking motif has been previously characterized in the mammalian PDE4D phosphodiesterase. The overexpression of RegA with alterations to this docking motif (RegA) restored RegA function to cells based on developmental phenotypes, but low-level expression of RegA from the endogenous promoter failed to rescue wild-type morphogenesis. Co-immunoprecipitation analysis indicated that Erk2 associates with both RegA and RegA, suggesting the docking motif is not required for this association. Epistasis analysis between and the only other MAPK, , suggests Erk1 and RegA can function in different pathways but that some phenotypes may require cAMP signalling. These results imply that MAPK downregulation of RegA in is accomplished through a different mechanism than MAPK regulation of cAMP-specific phosphodiesterases in mammalian cells and that the regulation in does not require a proximal MAPK docking motif.

Citing Articles

Copine C plays a role in adhesion and streaming in .

Nichols R, Ide A, Morrison C, Anger A, Buccilli M, Damer C Cell Adh Migr. 2024; 18(1):1-19.

PMID: 38378453 PMC: 10880500. DOI: 10.1080/19336918.2024.2315629.

An integrated, cross-regulation pathway model involving activating/adaptive and feed-forward/feed-back loops for directed oscillatory cAMP signal-relay/response during the development of .

Jaiswal P, Meena N, Chang F, Liao X, Kim L, Kimmel A Front Cell Dev Biol. 2024; 11:1263316.

PMID: 38357530 PMC: 10865387. DOI: 10.3389/fcell.2023.1263316.

A chemorepellent inhibits local Ras activation to inhibit pseudopod formation to bias cell movement away from the chemorepellent.

Kirolos S, Gomer R Mol Biol Cell. 2021; 33(1):ar9.

PMID: 34788129 PMC: 8886819. DOI: 10.1091/mbc.E20-10-0656.

Microbial Musings - February 2020.

Thomas G Microbiology (Reading). 2020; 166(2):93-95.

PMID: 32122459 PMC: 7398560. DOI: 10.1099/mic.0.000901.

References

Gaskins C, Maeda M, Firtel R . Identification and functional analysis of a developmentally regulated extracellular signal-regulated kinase gene in Dictyostelium discoideum. Mol Cell Biol. 1994; 14(10):6996-7012. PMC: 359230. DOI: 10.1128/mcb.14.10.6996-7012.1994. View

Maeda M, Lu S, Shaulsky G, Miyazaki Y, Kuwayama H, Tanaka Y . Periodic signaling controlled by an oscillatory circuit that includes protein kinases ERK2 and PKA. Science. 2004; 304(5672):875-8. DOI: 10.1126/science.1094647. View

Louis J, Ginsburg G, Kimmel A . The cAMP receptor CAR4 regulates axial patterning and cellular differentiation during late development of Dictyostelium. Genes Dev. 1994; 8(17):2086-96. DOI: 10.1101/gad.8.17.2086. View

Torres-Quesada O, Mayrhofer J, Stefan E . The many faces of compartmentalized PKA signalosomes. Cell Signal. 2017; 37:1-11. DOI: 10.1016/j.cellsig.2017.05.012. View

Mackenzie S, Baillie G, McPhee I, Mackenzie C, Seamons R, McSorley T . Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in Upstream Conserved Region 1 (UCR1). Br J Pharmacol. 2002; 136(3):421-33. PMC: 1573369. DOI: 10.1038/sj.bjp.0704743. View

Soberg K, Moen L, Skalhegg B, Laerdahl J . Evolution of the cAMP-dependent protein kinase (PKA) catalytic subunit isoforms. PLoS One. 2017; 12(7):e0181091. PMC: 5526564. DOI: 10.1371/journal.pone.0181091. View

Anjard C, Pinaud S, Kay R, Reymond C . Overexpression of Dd PK2 protein kinase causes rapid development and affects the intracellular cAMP pathway of Dictyostelium discoideum. Development. 1992; 115(3):785-90. DOI: 10.1242/dev.115.3.785. View

Wang H, Peng M, Chen Y, Geng J, Robinson H, Houslay M . Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochem J. 2007; 408(2):193-201. PMC: 2267353. DOI: 10.1042/BJ20070970. View

Edwards H, Christian F, Baillie G . cAMP: novel concepts in compartmentalised signalling. Semin Cell Dev Biol. 2011; 23(2):181-90. DOI: 10.1016/j.semcdb.2011.09.005. View

10.

Houslay M . Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci. 2009; 35(2):91-100. DOI: 10.1016/j.tibs.2009.09.007. View

11.

Wessels D, Zhang H, Reynolds J, Daniels K, Heid P, Lu S . The internal phosphodiesterase RegA is essential for the suppression of lateral pseudopods during Dictyostelium chemotaxis. Mol Biol Cell. 2000; 11(8):2803-20. PMC: 14957. DOI: 10.1091/mbc.11.8.2803. View

12.

Barber R, Baillie G, Bergmann R, Shepherd M, Sepper R, Houslay M . Differential expression of PDE4 cAMP phosphodiesterase isoforms in inflammatory cells of smokers with COPD, smokers without COPD, and nonsmokers. Am J Physiol Lung Cell Mol Physiol. 2004; 287(2):L332-43. DOI: 10.1152/ajplung.00384.2003. View

13.

Remenyi A, Good M, Bhattacharyya R, Lim W . The role of docking interactions in mediating signaling input, output, and discrimination in the yeast MAPK network. Mol Cell. 2005; 20(6):951-62. DOI: 10.1016/j.molcel.2005.10.030. View

14.

Schwebs D, Hadwiger J . The Dictyostelium MAPK ERK1 is phosphorylated in a secondary response to early developmental signaling. Cell Signal. 2014; 27(1):147-55. PMC: 4314436. DOI: 10.1016/j.cellsig.2014.10.009. View

15.

Baillie G . Compartmentalized signalling: spatial regulation of cAMP by the action of compartmentalized phosphodiesterases. FEBS J. 2009; 276(7):1790-9. DOI: 10.1111/j.1742-4658.2009.06926.x. View

16.

Ma H, Gamper M, Parent C, Firtel R . The Dictyostelium MAP kinase kinase DdMEK1 regulates chemotaxis and is essential for chemoattractant-mediated activation of guanylyl cyclase. EMBO J. 1997; 16(14):4317-32. PMC: 1170058. DOI: 10.1093/emboj/16.14.4317. View

17.

Thomason P, Traynor D, Stock J, Kay R . The RdeA-RegA system, a eukaryotic phospho-relay controlling cAMP breakdown. J Biol Chem. 1999; 274(39):27379-84. DOI: 10.1074/jbc.274.39.27379. View

18.

Zhang H, Heid P, Wessels D, Daniels K, Pham T, Loomis W . Constitutively active protein kinase A disrupts motility and chemotaxis in Dictyostelium discoideum. Eukaryot Cell. 2003; 2(1):62-75. PMC: 141174. DOI: 10.1128/EC.2.1.62-75.2003. View

19.

Hadwiger J . Developmental morphology and chemotactic responses are dependent on G alpha subunit specificity in Dictyostelium. Dev Biol. 2007; 312(1):1-12. PMC: 2176082. DOI: 10.1016/j.ydbio.2007.08.017. View

20.

G Williams J, Harwood A, Hopper N, Simon M, Bouzid S, Veron M . Regulation of Dictyostelium morphogenesis by cAMP-dependent protein kinase. Philos Trans R Soc Lond B Biol Sci. 1993; 340(1293):305-13. DOI: 10.1098/rstb.1993.0072. View