Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.706819
Title: Bimodal antagonism of PKA by ARHGAP36
Author: Eccles, R. L.
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Abstract:
PKA is a ubiquitous kinase whose activity is controlled by the second messenger cAMP downstream of GPCR signalling. PKA is a tetrameric holoenzyme composed of a homodimer of regulatory subunits (PKAR) which each bind and inhibit a catalytic subunit (PKAC). In this conformation the enzyme is inactive. Upon cAMP binding to the regulatory subunits, the catalytic subunits are released and can phosphorylate their substrates. Regulation of PKA is mainly centred around PKAR, in a large part via binding of the A-kinase anchoring proteins (AKAPs). Here I characterise a novel Rho GAP, ARHGAP36, and describe how it directly binds the PKA catalytic subunits. This binding is via a pseudosubstrate motif, which inhibits PKAC activity by blocking access to substrates. In addition to this, ARHGAP36 also mediates polyubiquitylation and degradation of PKAC. This is the first description of ubiquitin-mediated degradation of PKAC. Surprisingly for a cytosolic protein, degradation is not mediated by the proteasome but by the endolysosomal pathway, which is usually reserved for transmembrane proteins. This bimodal antagonism of PKAC by ARHGAP36 leads to suppression of a variety of PKA signalling responses downstream. I found that ARHGAP36 expression is developmentally regulated and restricted to embryonic skeletal muscle. It is, however, upregulated in neuroblastoma cell lines, where I could show that ARHGAP36 modulates PKAC activity and stability in an endogenous setting.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.706819  DOI: Not available
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