Regulation of Protein Kinase C-related Protein Kinase 2 (PRK2) by an Intermolecular PRK2-PRK2 Interaction Mediated by Its N-terminal Domain

• Published in: The Journal of biological chemistry 2012-06, Vol.287 (24), p.20590-20602
• Main Authors: Bauer, Angelika F., Sonzogni, Silvina, Meyer, Lucas, Zeuzem, Stefan, Piiper, Albrecht, Biondi, Ricardo M., Neimanis, Sonja
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Enzyme Activation - physiology; Enzymology; HEK293 Cells; Humans; Phosphatidylinositol-dependent Kinase-1 (PDK1); Phosphorylation - physiology; Protein Conformation; Protein Kinase C (PKC); Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein Kinases; Protein Multimerization - physiology; Protein Phosphorylation; Protein Structure, Secondary; Protein Structure, Tertiary; Protein-Protein Interactions; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.327437

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. Protein kinase C-related kinases (PRKs) are involved in the development of cancer and hepatitis C. N-terminal domains of PRK2 inhibit the interaction with its upstream kinase and are responsible for a dimerization that inhibits PRK2 activity. PRK2 regulation requires a cross-talk between the N- and C-terminal domains. The results provide new perspectives to pharmacologically target PRK2.