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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-47741

Schläfli, P; Tröger, J; Eckhardt, K; Borter, E; Spielmann, P; Wenger, R H (2011). Substrate preference and phosphatidylinositol monophosphate inhibition of the catalytic domain of the PAS kinase PASKIN. FEBS Journal, 278(10):1757-1768.

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Abstract

The PAS domain serine/threonine kinase PASKIN, or PAS kinase, links energy flux and protein
synthesis in yeast, regulates glycogen synthesis and protein translation in mammals, and might be
involved in insulin regulation in the pancreas. According to the current model, binding of a putative
ligand to the PAS domain disinhibits the kinase domain, leading to PASKIN autophosphorylation and
increased kinase activity. Up to date, only synthetic but no endogenous PASKIN ligands have been
reported. Here, we identified a number of novel PASKIN kinase targets, including ribosomal protein
S6. Together with our previous identification of eukaryotic translation elongation factor eEF1A1, this
suggests a role for PASKIN in the regulation of mammalian protein translation. While searching for
endogenous PASKIN ligands, we found that various phospholipids can bind PASKIN and stimulate its
autophosphorylation. Interestingly, strongest binding and autophosphorylation was achieved with
monophosphorylated phosphatidylinositols. However, stimulated PASKIN autophosphorylation did
not correlate with ribosomal protein S6 and eEF1A1 target phosphorylation. Whereas
autophosphorylation was enhanced by monophosphorylated phosphatidylinositols, di- and triphosphorylated
phosphatidylinositols inhibited autophosphorylation. In contrast, target
phosphorylation was always inhibited, with highest efficiency of di- and tri-phosphorylated
phosphatidylinositols. Since phosphatidylinositol monophosphates were found to interact with the
kinase rather than with the PAS domain, these data suggest a multi-ligand regulation of PASKIN
activity, including a still unknown PAS domain binding/activating ligand and kinase domain binding
modulatory phosphatidylinositol phosphates.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
DDC:570 Life sciences; biology
610 Medicine & health
Date:2011
Deposited On:24 Mar 2011 14:19
Last Modified:27 Nov 2013 22:54
Publisher:Wiley-Blackwell
ISSN:1742-464X
Additional Information:The definitive version is available at www.blackwell-synergy.com
Publisher DOI:10.1111/j.1742-4658.2011.08100.x
PubMed ID:21418524
Citations:Web of Science®. Times Cited: 3
Google Scholar™
Scopus®. Citation Count: 3

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