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Role of a novel regulator of p38 stress-activated MAP kinase signalling

Reference	BB/C512302/1
Principal Investigator / Supervisor	Dr Alan Whitmarsh
Co-Investigators / Co-Supervisors
Institution	The University of Manchester
Department	Life Sciences
Funding type	Research
Value (£)	211,876
Status	Completed
Type	Research Grant
Start date	01/09/2005
End date	31/08/2008
Duration	36 months

Abstract

Extracellular signals are sensed at the surface of cells and this information is transmitted via intracellular signalling pathways to particular targets within the cell. The specificity of these pathways needs to be tightly controlled in order for appropriate physiological responses to be elicited. An important mechanism for controlling signalling specificity is by scaffold or regulatory proteins binding to signalling molecules and regulating their activities and cell localisation. The p38 MAP kinase pathway is one of the major stress-signalling pathways in cells and is implicated in many processes including inflammatory response, apoptosis, cell differentiation and cell cycle regulation. We have identified a novel binding partner for p28 MAPK that is highly abundant in muscle and regulates p38 phosphorylation and activation of the transcription factor ATF-2. This protein, p38-interacting protein-1 (PIP-1), is evolutionary conserved and genetic studies of its homologue in fission yeast has demonstrated it to be a critical component of a stress-response pathway. We propose to characterise the molecular determinants of the PIP-1 interaction with p38, their localisation in cells and the mechanism by which PIP-1 targets p38 to ATF-2 and potentially other transcription factors. In addition, we plan to elucidate the function of PIP-1 in muscle cell differentiation and stress responses. For these studies we will use a previously characterised model of p38 dependent muscle cell differentiation, C2C12 cells, and primary cardiomyocytes which have been extensively used to characterise p38-mediated stress responses. The molecular tools we will employ include the ectopic expression of PIP-1 mutants that are impaired for p38 binding or signalling, cell permeable peptides that block PIP-1 binding to p38, and the knockdown of PIP-1 expression in cells by siRNA. Overall, the study will enhance our understanding of the p38 signalling pathway and will provide important new insights into the molecular mechanisms underlying signalling specificity and muscle responses.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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