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Title: Integrin affinity modulation by Ras signalling molecules
Author: Lad, Yatishkumar
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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In this thesis I have sought to understand the mechanism by which H-Ras and its effectors modulate integrin affinity. H-Ras is a member of the Ras superfamily of small GTP binding proteins. Expression of the constitutively active variant of H-Ras (Ras G12V) within an integrin affinity reporter system (αβ-py cells) reduced integrin affinity (suppressed integrin). Ras effector mutants revealed that integrin suppression is mediated by Raf-dependent and Raf-independent signalling pathways. Raf-independent signalling pathways activated by Ral-GEFs and PI3-kinase were not recognisable for integrin suppression. An active variant of R-Ras (R-Ras G38V) reversed integrin suppression by both Raf-dependent and - independent pathways, indicating that these pathways may converge at a point proximal to the integrin. Raf initiates a protein signalling cascade leading to ERK activation that is responsible for many of the Ras/Raf-dependent biological functions. However, Raf-dependent integrin suppression was insensitive to MEK inhibition with the PD098059 compound. A novel Raf mutant (T481A) that fails to bind to MEK was also capable of mediating integrin suppression in the absence of ERK activation. Surprisingly, Raf-BxB T481A-mediated integrin suppression was sensitive to expression of MKP-1. Taken together it is proposed that Raf may mediate integrin suppression via a MEK-independent pathway that may utilise a member of the MAP kinase superfamily. In conclusion, integrin suppression by Ras is mediated by both Raf-independent and dependent pathways. Signalling by Raf may utilise components other than those present in the classical Ras to ERK protein cascade.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available