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The expansion of GPCR transactivation-dependent signalling to include serine/threonine kinase receptors represents a new cell signalling frontier

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Abstract

G protein-coupled receptor (GPCR) signalling is mediated through transactivation-independent signalling pathways or the transactivation of protein tyrosine kinase receptors and the recently reported activation of the serine/threonine kinase receptors, most notably the transforming growth factor-β receptor family. Since the original observation of GPCR transactivation of protein tyrosine kinase receptors, there has been considerable work on the mechanism of transactivation and several pathways are prominent. These pathways include the “triple membrane bypass” pathway and the generation of reactive oxygen species. The recent recognition of GPCR transactivation of serine/threonine kinase receptors enormously broadens the GPCR signalling paradigm. It may be predicted that the transactivation of serine/threonine kinase receptors would have mechanistic similarities with transactivation of tyrosine kinase pathways; however, initial studies suggest that these two transactivation pathways are mechanistically distinct. Important questions are the relative importance of tyrosine and serine/threonine transactivation pathways, the contribution of transactivation to overall GPCR signalling, mechanisms of transactivation and the range of cell types in which this phenomenon occurs. The ultimate significance of transactivation-dependent signalling remains to be defined but it appears to be prominent and if so will represent a new cell signalling frontier.

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Acknowledgments

This study was supported by a National Heart Foundation of Australia grant-in-aid (PJL/NO). MAR is supported by the Academic Trainee Scholarship from the International Islamic University of Malaysia. We thank the Ministry of Foreign Experts of the Government of the People’s Republic of China for support by way of High End Professor (Education) Award through Zhongshan (Sun Yat-sen) University (PJL).

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Authors and Affiliations

  1. Diabetes Complications Laboratory, Discipline of Pharmacy, School of Medical Sciences and Diabetes Complications Group, RMIT University, Bundoora, VIC, 3083, Australia

    Danielle Kamato, Muhamad Ashraf Rostam, Rebekah Bernard, Daniel Guidone, Narin Osman & Peter J. Little

  2. Discipline of Cell Biology and Anatomy, School of Medical Sciences and Health Innovations Research Institute, Bundoora, VIC, 3083, Australia

    Terrence J. Piva

  3. School of Applied Sciences, RMIT University, Bundoora, VIC, 3083, Australia

    Nitin Mantri

  4. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre and School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People’s Republic of China

    Wenhua Zheng

  5. Department of Medicine, Nursing and Health Sciences and Immunology, Monash University School of Medicine (Central and Eastern Clinical School, Alfred Health), Prahran, VIC, 3004, Australia

    Narin Osman & Peter J. Little

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  1. Danielle Kamato
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  9. Peter J. Little
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Kamato, D., Rostam, M.A., Bernard, R. et al. The expansion of GPCR transactivation-dependent signalling to include serine/threonine kinase receptors represents a new cell signalling frontier. Cell. Mol. Life Sci. 72, 799–808 (2015). https://doi.org/10.1007/s00018-014-1775-0

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