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| Subject Categories: Signal Transduction | Proteins |
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| The EMBO Journal
(2008) 27, 1073–1084, doi:10.1038/emboj.2008.33 Published online 6 March 2008 |
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| Proteolysis of AKAP121 regulates mitochondrial activity during cellular hypoxia and brain ischaemia |
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| Annalisa Carlucci1, Annagrazia Adornetto2, Antonella Scorziello2, Davide Viggiano2, Mariapaola Foca1, Ornella Cuomo2, Lucio Annunziato2, Max Gottesman3 and Antonio Feliciello1 |
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1 Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università "Federico II", Naples, Italy 2 Divisione di Farmacologia, Dipartimento di Neuroscienze, Università "Federico II", Naples, Italy 3 Institute of Cancer Research, Columbia University, New York, NY, USA To whom correspondence should be addressed Antonio Feliciello, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università Federico II, via S Pansini, 5, Naples 80131, Italy. Tel.: +39 081 7463 615; Fax: +39 081 7463 252; E-mail: feliciel@unina.it Received 5 September 2007; Accepted 8 February 2008; Published online 6 March 2008. |
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| Abstract |
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| 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. |
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| Keywords: AKAP, hypoxia, mitochondria, Siah2, ubiquitin |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHJournal of Cerebral Blood Flow & Metabolism Original Article Proteolysis of AKAP121 regulates mitochondrial activity during cellular hypoxia and brain ischaemia The EMBO Journal Article Journal of Investigative Dermatology Original Article Oncogene Original Article Oncogene Original Article |
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