Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Proteolysis of AKAP121 regulates mitochondrial activity during cellular hypoxia and brain ischaemia.

The EMBO journal | Apr 9, 2008

http://www.ncbi.nlm.nih.gov/pubmed/18323779

A-kinase anchor protein 121 (AKAP121) assembles a multivalent signalling complex on the outer mitochondrial membrane that controls persistence and amplitude of cAMP and src signalling to mitochondria, and plays an essential role in oxidative metabolism and cell survival. Here, we show that AKAP121 levels are regulated post-translationally by the ubiquitin/proteasome pathway. Seven In-Absentia Homolog 2 (Siah2), an E3-ubiquitin ligase whose expression is induced in hypoxic conditions, formed a complex and degraded AKAP121. In addition, we show that overexpression of Siah2 or oxygen and glucose deprivation (OGD) promotes Siah2-mediated ubiquitination and proteolysis of AKAP121. Upregulation of Siah2, by modulation of the cellular levels of AKAP121, significantly affects mitochondrial activity assessed as mitochondrial membrane potential and oxidative capacity. Also during cerebral ischaemia, AKAP121 is degraded in a Siah2-dependent manner. These findings reveal a novel mechanism of attenuation of cAMP/PKA signaling, which occurs at the distal sites of signal generation mediated by proteolysis of an AKAP scaffold protein. By regulating the stability of AKAP121-signalling complex at mitochondria, cells efficiently and rapidly adapt oxidative metabolism to fluctuations in oxygen availability.

Pubmed ID: 18323779 RIS Download

Mesh terms: A Kinase Anchor Proteins | Animals | Brain Ischemia | Cell Hypoxia | Glucose | Humans | Male | Membrane Potential, Mitochondrial | Mice | Middle Cerebral Artery | Mitochondria | Models, Biological | NIH 3T3 Cells | Nuclear Proteins | Oxygen | Proteasome Endopeptidase Complex | Protein Binding | Protein Processing, Post-Translational | Rats | Rats, Wistar | Signal Transduction | Ubiquitin-Protein Ligases | Ubiquitination

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

None

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.