title: Regulation of protein kinase C-related protein kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by Its N-terminal domain.
abstract: Protein kinase C-related protein kinases (PRKs) are effectors of the Rho family of small GTPases and play a role in the development of diseases such as prostate cancer and hepatitis C. Here we examined the mechanism underlying the regulation of PRK2 by its N-terminal region. We show that the N-terminal region of PRK2 prevents the interaction with its upstream kinase, the 3-phosphoinositide-dependent kinase 1 (PDK1), which phosphorylates the activation loop of PRK2. We confirm that the N-terminal region directly inhibits the kinase activity of PRK2. However, in contrast to previous models, our data indicate that this inhibition is mediated in trans through an intermolecular PRK2-PRK2 interaction. Our results also suggest that amino acids 487-501, located in the linker region between the N-terminal domains and the catalytic domain, contribute to the PRK2-PRK2 dimer formation. This dimerization is further supported by other N-terminal domains. Additionally, we provide evidence that the region C-terminal to the catalytic domain intramolecularly activates PRK2. Finally, we discovered that the catalytic domain mediates a cross-talk between the inhibitory N-terminal region and the activating C-terminal region. The results presented here describe a novel mechanism of regulation among AGC kinases and offer new insights into potential approaches to pharmacologically regulate PRK2.
authors.affiliation: Department of Internal Medicine I, Research Group PhosphoSites, Goethe University Hospital Frankfurt, Frankfurt 60590, Germany.
authors.forename: Angelika F
authors.initials: AF
authors.lastname: Bauer
authors.forename: Silvina
authors.initials: S
authors.lastname: Sonzogni
authors.forename: Lucas
authors.initials: L
authors.lastname: Meyer
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Albrecht
authors.initials: A
authors.lastname: Piiper
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Biondi
authors.forename: Sonja
authors.initials: S
authors.lastname: Neimanis
mesh_terms: D004789:Enzyme Activation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation / Q000502:physiology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C061570:protein kinase N; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C