Human protein phosphatase 5 dissociates from heat-shock proteins and is proteolytically activated in response to arachidonic acid and the microtubule-depolymerizing drug nocodazole.
Ppp5 (protein phosphatase 5) is a serine/threonine protein phosphatase that has been conserved throughout eukaryotic evolution. In mammalian cells, FLAG-tagged Ppp5 and endogenous Ppp5 are found to interact with endogenous Hsp (heat-shock protein) 70, as well as Hsp90. Incubation of cells with arachidonic acid or the microtubule-depolymerizing agent, nocodazole, causes loss of interaction of Hsp70 and Hsp90 with FLAG-tagged Ppp5 and increase of Ppp5 activity. In response to the same treatments, endogenous Ppp5 undergoes proteolytic cleavage of the N- and C-termini, with the subsequent appearance of high-molecular-mass species. The results indicate that Ppp5 is activated by proteolysis on dissociation from Hsps, and is destroyed via the proteasome after ubiquitination. Cleavage at the C-terminus removes a nuclear localization sequence, allowing these active cleaved forms of Ppp5 to translocate to the cytoplasm. The response of Ppp5 to arachidonic acid and nocodazole suggests that Ppp5 may be required for stress-related processes that can sometimes cause cell-cycle arrest, and leads to the first description for in vivo regulation of Ppp5 activity.
Zeke
Tamás
T
Medical Research Council Protein Phosphorylation Unit, Division of Cell Signalling, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
Morrice
Nick
N
Vázquez-Martin
Cristina
C
Cohen
Patricia T W
PT
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D002453:Cell Cycle; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics; D015739:Nocodazole / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects
D000970:Antineoplastic Agents; D006360:Heat-Shock Proteins; D009687:Nuclear Proteins; D016718:Arachidonic Acid; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5; D015739:Nocodazole