PKA phosphorylation of p62/SQSTM1 regulates PB1 domain interaction partner binding

Christian, F. , Krause, E., Houslay, M. D. and Baillie, G. (2014) PKA phosphorylation of p62/SQSTM1 regulates PB1 domain interaction partner binding. Biochimica et Biophysica Acta: Molecular Cell Research, 1843(11), pp. 2765-2774. (doi:10.1016/j.bbamcr.2014.07.021) (PMID:25110345)

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p62, also known as SQSTM1, is a multi-domain signalling scaffold protein involved in numerous critical cellular functions such as autophagy, apoptosis and inflammation. Crucial interactions relevant to these functions are mediated by the N-terminal Phox and Bem1p (PB1) domain, which is divided into two interaction surfaces, one of predominantly acidic and one of basic character. Most known interaction partners, including atypical protein kinase C (aPKC), bind to the basic surface, and acidic–basic interactions at this interface also allow for p62 homopolymerisation. We identify here that the coupling of p62 to the cAMP signalling system is conferred by both the direct binding of cAMP degrading phosphodiesterase-4 (PDE4) to the acidic surface of the p62 PB1 domain and the phosphorylation of the basic surface of this domain by cAMP-dependent protein kinase (PKA). Such phosphorylation is a previously unknown means of regulating PB1 domain interaction partnerships by disrupting the interaction of p62 with basic surface binding partners, such as aPKCs, as well as p62 homopolymerisation. Thus, we uncover a new regulatory mechanism that connects cAMP signalling with the p62 multi-domain signalling scaffold and autophagy cargo receptor protein.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Baillie, Professor George and Houslay, Professor Miles and Christian, Dr Frank
Authors: Christian, F., Krause, E., Houslay, M. D., and Baillie, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Biochimica et Biophysica Acta: Molecular Cell Research
ISSN (Online):1879-2596

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765RI NEUROSCIENCE & PSYCHOLOGY