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Title: The regulation and role of PAK1 in macrophages
Author: Smith, Stephen
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2006
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The p21-activated kinases (PAKs) are a family of serine/threonine kinases that are activated by the Rho GTPases, Rac1-3, Cdc42, Chp, TC10 and Wrch-1, as well as a number of lipids and PAK-interacting proteins. PAKs have been implicated in a variety of cellular processes including cell polarisation, migration, chemotaxis and gene transcription. The aim of this study was to determine the regulation and function of PAK1, using bone marrow-derived macrophages (BMMs) as a model system. CSF-1 stimulation of BMMs induced rapid phosphorylation and activation of PAK1, and CSF-1 and TNFa also promoted an increase in PAK1 protein levels after 2 to 5 hours. The rise in PAK1 protein was not due to changes in gene transcription, mRNA translation or reduced proteasomal degradation. Wildtype and PAK1"7" BMMs were compared to determine the roles of PAK1 in a number of macrophage functions. PAK1 was required for maximal ERK, p38 and JNK activation in response to CSF-1 although it did not appear to signal via c-Raf or MEK1. PAK1 phosphorylated Op18 and LIMK downstream of CSF-1, which regulate microtubule and actin reorganisation respectively. PAK1 also regulated MLC phosphorylation although this was not a CSF-1-induced response. PAK1_/" BMMs adhered more rapidly than WT BMMs and transiently spread to a greater area than WT BMMs. PAK1 promotion of ERK activity at the lamellipodial edge was required for the stability of lamellipodial extension during cell spreading with a greater number of smaller lamellipodia produced in PAK1"7" BMMs compared to WT BMMs. However, PAK2, active Cdc42, total ERK, £-PIX and Rac1 all localised normally at the cell periphery in spreading PAK1"7" BMMs. PAK1 was also required for membrane ruffling after CSF-1 stimulation but was dispensable for macrophage polarisation, migration and chemotaxis towards CSF-1. PAK1, therefore, contributes to CSF-1 and cell adhesion induced signalling in macrophages.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available