Competition Between Grb2 and Plcγ1 For Binding to Fgfr2 Regulates Phospholipase and Pten Activity, Leading to Cell Invasion and Proliferation

<p>@font-face { font-family: "Arial"; }@font-face { font-family: "Calibri"; }p.MsoNormal, li.MsoNormal, div.MsoNormal { margin: 0in 0in 0.0001pt; font-size: 12pt; font-family: Arial; }p.MsoNoSpacing, li.MsoNoSpacing, div.MsoNoSpacing { margin: 0in 0in 0.0001pt; font-size: 12pt; font-family: Arial; }div.Section1 { page: Section1; }</p> <p>Fluctuations in the relative concentrations of proteins in non-stimulated cells can lead to aberrant signaling. In a novel interaction, the SH3 domain of Plcγ1 competes with the SH3 domain of Grb2 for binding to FGFR2 in a concentration-dependent manner. Consequently, reduction of cellular concentrations of Grb2 lead to receptor-dependent recruitment of unphosphorylated Plcγ1. Bringing of the phospholipase to the membrane in this way upregulates its activity, resulting in increased PIP₂ turnover to IP₃ and DAG resulting in elevated cellular calcium levels. These signaling events increase cell migration and invasion. A further consequence of the depletion of PIP₂is the inhibition of PTEN phosphatase activity. Inhibition of PTEN activity leads to the accumulation of PIP₃, which recruits Akt leading to its phosphorylation and activation. Therefore, depletion of Grb2 indirectly leads to activation of the proto-oncogene Akt inducing phenotypic alterations characteristic of tumorigenesis including anchorage-independent cell growth and tumor formation in mice models.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• timsah, zahra

Contributors dc:contributor

• john ladbury
• elsa flores
• jeffrey frost

• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/422

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1462