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

Abstract

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

Conserved Modular Domains Team up to Latch-open Active Protein Kinase Cα

“…This interaction has been shown to dramatically enhance PDK1 catalytic activity and cellular function (34 between the catalytic and PH domains has been speculated to down-regulate PDK1 activity in cells (60). In the protein kinase C-related protein 2 (PRK2) an inhibitory homodimerization occurs between the N-terminal regulatory domains (including a C2 domain) and the catalytic domains (26). The AGC Rhoassociated kinase I and II (ROCKI and -II) are also observed forming a homodimer between regulatory domains and the C-tail (61).…”

“…The band is consistent with PKC␣-FLAG running between the expected molecular weight of dimeric and trimeric PKC␣. A recent report used a similar Cys-Cys cross-linking assay (26) for the PKC-related protein (PRK) kinase and observed a homodimer running above its expected molecular weight. Based on this previous observation and the presence of a single higher molecular weight band, PKC␣ likely homodimerizes rather than forms a higher order oligomer.…”

Targeting protein kinase C in sarcoma

“…1) [22,23]. For the PKN kinases, controversy remains over identification of a pseudo-substrate motif within the HR1 repeat region [24]; alternative autoinhibitory dimerization has also been proposed for PKN2 [25]. Interaction with membranes, specific lipid activators and/or protein partners serves to disengage the pseudo-substrate from the active site to allow target substrate access and trans-phosphorylation.…”

CagA ofHelicobacter pyloriinteracts with and inhibits the serine-threonine kinase PRK2

“…Phosphoinositide‐dependent kinase 1 (PDK1) was shown to activate PRK1 and also PRK2 activities via phosphorylation of the activation loop (Belham et al ., ; Dettori et al ., ). The amino‐terminal region of PRK2 strongly inhibits PRK2 kinase activity by mediating PRK2–PRK2 oligomerization, which blocks PDK1 binding to the C‐terminal PDK1 interacting fragment (PIF) of PRK2 thereby preventing PRK2 activation (Bauer et al ., ). This mechanism is different from the regulation of other PKC‐type kinases that are typically activated by PDK1 via intramolecular binding of the amino‐termini.…”

“…This mechanism is different from the regulation of other PKC‐type kinases that are typically activated by PDK1 via intramolecular binding of the amino‐termini. PRK2 activation requires binding of Rho‐GTP to the ACC1 domain, which then causes the release of the PIF fragment allowing PDK1 binding and phosphorylation of the PRK2 activation loop (Bauer et al ., ). After further phosphorylation events, PDK1 dissociates and the active kinase structure is stabilized by intramolecular interaction between the PIF fragment and the catalytic domain.…”