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Dexamethasone-induced Ras protein 1 negatively regulates protein kinase C delta: implications for adenylyl cyclase 2

Chau H Nguyen1, Val J Watts

  • 1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, RHPH 210, West Lafayette, IN 47907, USA.

Molecular Pharmacology
|February 21, 2006
PubMed

Insights

Dexamethasone-induced Ras protein 1 (Dexras1) negatively regulates protein kinase C (PKC) delta, impacting adenylyl cyclase 2 (AC2) signaling. This Dexras1 interaction with PKC delta is isoprenylation-dependent, modulating AC2 activity.

Area of Science:

  • Cellular signaling and signal transduction pathways.
  • Molecular mechanisms of enzyme regulation.
  • G protein-coupled receptor signaling.

Background:

  • Adenylyl cyclase type 2 (AC2) is a key enzyme in cellular signaling, modulated by various pathways including Gbetagamma and protein kinase C (PKC).
  • Dexamethasone-induced Ras protein 1 (Dexras1) has been implicated in blocking receptor-mediated Gbetagamma signaling.
  • The precise role of Dexras1 in regulating PKC isoforms and their downstream effects on AC2 remains to be fully elucidated.

Purpose of the Study:

  • To identify Dexras1 as a negative regulator of PKC delta.
  • To investigate the functional consequences of Dexras1-PKC delta interaction on AC2 signaling.
  • To determine the mechanism and cellular localization of Dexras1's regulatory action on PKC delta and AC2.

Main Methods:

  • Expression of Dexras1 in human embryonic kidney 293 cells.
  • Assessment of AC2 activity in response to dopamine D2 receptor stimulation and phorbol 12-myristate 13-acetate (PMA).
  • Analysis of PKC delta autophosphorylation and kinase activity using co-immunoprecipitation and [gamma-32P]ATP incorporation.
  • Investigation of the role of isoprenylation using a farnesyltransferase inhibitor (FTI-277) and a CAAX box-deficient mutant (C277S).

Main Results:

  • Dexras1 expression abolished dopamine D2 receptor-mediated potentiation of AC2 activity and reduced PMA-stimulated AC2 activity.
  • Dexras1 specifically interfered with PKC delta autophosphorylation and kinase activity, but not PKC alpha or epsilon.
  • Dexras1 co-immunoprecipitated with PKC delta at the cellular membrane, and this interaction was dependent on Dexras1 isoprenylation.
  • Dexras1 did not affect Galpha(s)-mediated cAMP accumulation or PKC delta membrane translocation.

Conclusions:

  • Dexras1 acts as a negative regulator of PKC delta activity through an isoprenylation-dependent mechanism at the cellular membrane.
  • Dexras1 indirectly modulates AC2 activity by inhibiting both Gbetagamma- and PKC delta-mediated signaling pathways.
  • This study reveals a novel role for Dexras1 in cellular signal transduction by linking Gbetagamma and PKC signaling to AC2 regulation.

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