A Study Examining the Role of Rho Family GTPases in the Intracellular Targeting of Src Kinase During Cell Polarisation and Migration

Timpson, Paul (2002) A Study Examining the Role of Rho Family GTPases in the Intracellular Targeting of Src Kinase During Cell Polarisation and Migration. PhD thesis, University of Glasgow.

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Abstract

The ability of a cell to polarise and move is governed by re-modelling of the cellular adhesion/cytoskeletal network that is in turn controlled by the Rho family of small GTPases. However, it is not known what signals lie downstream of Rad and Cdc42 during peripheral adhesion re-modelling that are required for directional migration. We show here that individual members of the Rho family, RhoA, Rac1 and Cdc42, direct the specific intracellular targeting of c-Src tyrosine kinase to focal adhesions, lamellipodia or filopodia, respectively, and that the adaptor function of c-Src (the combined SH3/SH2 domains coupled to green fluorescent protein) is sufficient for targeting. Furthermore, Src's catalytic activity is absolutely required at these peripheral cell-matrix attachment sites for adhesion re-modelling that converts RhoA-dependent focal adhesions into smaller focal complexes along Rad-induced lamellipodia or Cdc42-induced filopodia. Consequently, cells in which kinase-deficient c-Src occupies peripheral adhesion sites exhibit impaired polarisation towards migratory stimuli and reduced motility. Our findings demonstrate that individual Rho GTPases specify Src's exact peripheral localisation, and that RhoA, Rac1 and Cdc42 cannot co-ordinate cell structural changes and directed cell migration when Src is present at adhesion sites in an inactive form. Src's role, which involves phosphorylation of adhesion substrates including FAK, is to induce the necessary adhesion re-modelling downstream of Rac1 and Cdc42 during migratory cell responses.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Margaret Frame
Keywords: Cellular biology
Date of Award: 2002
Depositing User: Enlighten Team
Unique ID: glathesis:2002-75760
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 18:15
Last Modified: 19 Nov 2019 18:15
URI: http://theses.gla.ac.uk/id/eprint/75760

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