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Co-ordinate regulation of the microtubule anchoring protein Nlp by the Nek2 and Plk1 centrosome kinases

Reference	BB/C000013/1
Principal Investigator / Supervisor	Professor Andrew Fry
Co-Investigators / Co-Supervisors
Institution	University of Leicester
Department	Biochemistry
Funding type	Research
Value (£)	233,492
Status	Completed
Type	Research Grant
Start date	01/03/2005
End date	29/02/2008
Duration	36 months

Abstract

Entry into mitosis is accompanied by a major reorganisation of the microtubule (MT) network and involves post-translational modification of proteins implicated in MT stability, nucleation and anchoring. Recently, Nigg and colleagues (Martinsried, Germany) described the identification of a novel human protein, called Nlp, that binds to interphase centrosomes but not mitotic spindle poles. Nlp interacts with components of the g-tubulin ring complex providing evidence for a function in either MT nucleation or anchoring. Furthermore, Nlp could be phosphorylated by the centrosomal kinase Plk1 that is activated at the onset of mitosis. In collaboration with the Nigg group, we isolated a Xenopus laevis homologue of Nlp and, using specific antibodies, showed that X-Nlp localises specifically to the mother centriole, a site implicated in MT anchoring. X-Nlp is displaced from the mother centriole, but not degraded, at the G2/M transition supporting the hypothesis that its localisation is under the control of post-translational modification. Intriguingly, we found that human Nlp is also a substrate both in vitro and in vivo for the Nek2 protein kinase raising the possibility that its localisation and function are regulated through phosphorylation by Plk1 and Nek2. This is particularly important in light of recent data showing that binding of Plk1 to its substrates is promoted by prior phosphorylation at distinct sites from those targeted by Plk1. This project is therefore based upon testing the hypothesis that Nlp is required for MT anchoring during interphase and whose localisation is co-ordinately regulated upon mitotic entry by the Plk1 and Nek2 kinases. We will use a broad range of approaches, as detailed in the objectives, to investigate the timely questions of how Nlp associates with the centrosome structure, whether Nlp is necessary and sufficient for MT anchoring, how Nek2 phosphorylation regulates Nlp and whether Nek2 acts as a priming kinase for regulating association of Nip with Plk1.

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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