Over 30 receptor-like kinases contain a guanylate cyclase (GC) catalytic centre embedded within the C-terminal region of their kinase domain in the model plant Arabidopsis. A number of the kinase GCs contain both functional kinase and GC activity in vitro and the natural ligands of these receptors stimulate increases in cGMP within isolated protoplasts. The GC activity could be described as a minor or moonlighting activity. We have also identified mammalian proteins that contain the novel GC centre embedded within kinase domains. One example is the interleukin 1 receptor-associated kinase 3 (IRAK3). We compare the GC functionality of the mammalian protein IRAK3 with the cytoplasmic domain of the plant prototype molecule, the phytosulfokine receptor 1 (PSKR1). We have developed homology models of these molecules and have undertaken in vitro experiments to compare their functionality and structural features. Recombinant IRAK3 produces cGMP at levels comparable to those produced by PSKR1, suggesting that IRAK3 contains GC activity. Our findings raise the possibility that kinase-GCs may switch between downstream kinase-mediated or cGMP-mediated signalling cascades to elicit desired outputs to particular stimuli. The challenge now lies in understanding the interaction between the GC and kinase domains and how these molecules utilize their dual functionality within cells.
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December 2014
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Conference Article|
November 17 2014
Comparison of moonlighting guanylate cyclases: roles in signal direction?
Lubna Freihat;
Lubna Freihat
*Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
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Victor Muleya;
Victor Muleya
*Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
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David T. Manallack;
David T. Manallack
*Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
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Janet I. Wheeler;
Janet I. Wheeler
*Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
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Helen R. Irving
Helen R. Irving
1
*Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
1To whom correspondence should be addressed (emailhelen.irving@monash.edu).
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Publisher: Portland Press Ltd
Received:
August 12 2014
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem Soc Trans (2014) 42 (6): 1773–1779.
Article history
Received:
August 12 2014
Citation
Lubna Freihat, Victor Muleya, David T. Manallack, Janet I. Wheeler, Helen R. Irving; Comparison of moonlighting guanylate cyclases: roles in signal direction?. Biochem Soc Trans 1 December 2014; 42 (6): 1773–1779. doi: https://doi.org/10.1042/BST20140223
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