Patel, Jayesh Chhotubai; (2001) Regulation of small GTPase function during phagocytosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Phagocytosis is the process whereby cells bind and engulf particulate materials via the localised remodelling of the actin cytoskeleton. Small GTPases of the Rho family have been widely implicated in co-ordinating actin dynamics during diverse cellular processes, including phagocytosis, yet the signalling mechanisms controlling their recruitment and activation remain unclear. This thesis investigates the signalling pathways involved in regulating small GTPase function during phagocytosis via two distinct receptors, the FcγR, which is known to require Cdc42 and Rac and the complement receptor 3 (CR3, αMβ2, CD11b/CD18), which is known to couple to Rho. Data is presented showing that in response to FcγR ligation, Cdc42 and Rac are activated. Moreover, the guanine nucleotide exchange factor, Vav translocates to nascent phagosomes and promotes GTP-loading on Rac, but not Cdc42. The Vav induced Rac activation proceeds independently of Cdc42 function suggesting distinct roles for each GTPase during engulfment. Moreover, inhibition of Vav exchange activity or of Cdc42 activity does not prevent Rac recruitment to sites of particle attachment. This suggests that Rac is recruited to Fcγ membrane receptors in its inactive, GDP-bound state and that Vav regulates phagocytosis through subsequent catalysis of GDP/GTP exchange on Rac. In contrast, phagocytosis via the integrin receptor CR3 (αMβ2) proceeds via a two-step mechanism involving inside-out signalling to activate the receptor and ligand directed engulfment. Evidence supporting independent roles for the cytoplasmic tails of CR3 in regulating these activities is presented, with the β2 (CD18) tail directing receptor activation and the αM (CD11b) tail promoting the activation of Rho, necessary for engulfment.

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