UCSF

This thesis examines multiple facets of the human epidermal growth factor receptor-3 (HER3) signaling. Receptor tyrosine kinases are typically activated through ligand-dependent homodimerization resulting in trans-autophosphorylation and subsequent kinase activation, resulting in phosphorylation of tyrosines which serve as recruitment sites for downstream signal transducers. These homomeric interactions are tightly regulated and occur only within RTK sub-families thereby limiting cross-activation between unrelated receptors. HER3 is one of four members of the EGFR/HER family of RTKs, consisting of EGFR, HER2, HER3, and HER4. This family of RTKs is activated through a unique mechanism where ligand binding drives formation of an asymmetric dimer in which one receptor, the “activator”, allosterically activates its partner, the “receiver”. Among this family, HER3 is unique in that it has mutations within several key residues that render it catalytically impaired. In spite of this, HER3 is able to signal by assuming the “activator” role when paired with EGFR, HER2, or HER4, leading to phosphorylation of the HER3 C-terminal tail. The tail of HER3 contains six direct binding sites for phosphatidylinositol-3 kinase (PI3K) recruitment resulting in its exceptional ability to potently activate the PI3K pathway.

The MET receptor, along with the Ron receptor, make up the MET receptor family. Like the HER family, the MET receptor also plays a role in cancer progression particularly in driving invasiveness and metastasis. The most common mechanism of activation of MET in cancer is through protein overexpression, often through genomic amplification. The MET receptor couples to activation of the MAPK and PI3K pathways through a bidentate binding site in its C-terminal domain which directly recruits Gab1. In cancers with MET overexpression, MET has also been found to drive phosphorylation of multiple other unrelated RTKs.

The first chapter of this thesis elucidates how overexpression of MET in cancer mediates phosphorylation of HER3 in the Golgi apparatus. The second chapter investigates the contributions of individual PI3K binding sites, and describes a new role for SHC, in activation of PI3K/Akt signaling by HER3.