Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

john ladbury

Committee Member

elsa flores

Committee Member

jeffrey frost

Committee Member

john hancock

Committee Member

gary gallick


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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 PIP2 is 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.