Biomedical Sciences Graduate Program | University of California, San Francisco

Background
Phosphotyrosine signaling regulates spacially defined cellular interactions in metazoans, enabling multicellular architecture, tissue development and homeostasis. A hallmark of cancer is the deregulation of phosphotyrosine signaling. This occurs through mutational activation, overexpression, or autocrine and paracrine ligand activation of members of the receptor or non-receptor families of tyrosine kinases. Deregulated tyrosine kinase signaling in cancer cells leads to cell behavior in betrayal of tissue homeostasis promoting malignant phenotypes such as invasion, angiogenesis, migration, and metastasis. A principal challenge of cancer biology is to understand how deregulated tyrosine kinase signaling promotes these phenotypes of malignancy.

Recent advances in pharmaceutical technologies have led to the development of selective inhibitors of receptor or non-receptor tyrosine kinases and a plethora of agents against a multitude of tyrosine kinase targets are now in various phases of preclinical and clinical development. Effective use of these agents in the treatment of cancer requires mechanistic understanding of cellular tyrosine kinase targets in order to develop rational hypotheses for the use of such inhibitors in specific cancer subtypes, to develop specific combinations to enhance their efficacies, and to understand mechanisms by which cancers escape or acquire resistance to such targeted therapies.

Our lab has been focusing on two of the tyrosine kinase families strongly implicated in human cancers; the Human Epidermal Growth Factor Receptor (HER) family of receptor tyrosine kinases and the Src family of non-receptor tyrosine kinases. We use in vitro biochemical assays, cell based signaling models, and in vivo mouse models to understand the signaling and tumorigenic functions of these kinases, and the effects of tyrosine kinase inhibitors on their signaling and tumorigenic functions. Our group is involved in numerous cross-disciplinary collaborations with colleagues in pharmaceutical chemistry, structural biology, mouse modeling, and functional imaging. When our laboratory studies suggest new hypotheses for the treatment of patients, we conduct clinical studies to test our hypotheses.

HER family
Overactivity of the HER family members EGFR or HER2 is seen in many cancers through gene amplification and overexpression, mutational activation of the kinase domains or the extracellular ligand-binding domains, or autocrine activating signaling loops. In particular, HER2 overexpression is potently transforming and amplification and overexpression of HER2 occurs in about 25% of breast cancers. Experimental evidence strongly supports the notion that HER2 is a principal oncogenic driver of these cancers, identifying it as a major target for anti-cancer drug development. Two decades of efforts have produced a number of HER2-targeting drugs but only modest clinical efficacy. Our laboratory is interested in understanding the resiliency of the HER2 oncoprotein, and in this effort we discovered that HER2-HER3 transactivation is considerably more difficult to inhibit using current drug therapies. This finding coincided with other studies identifying the catalytically inactive HER3 as a critical partner for HER2-driven transformation. Recent mechanistic studies have defined the allosteric mechanism that mediates kinase domain transactivation in this family, suggesting critically important functions of the HER3 kinase domain. These converging lines of evidence have redefined the driving oncoprotein in HER2 amplified tumors as the HER2-HER3 complex. A principal interest of our lab is to understand the complexities of this oncoprotein signaling dimer and determine the structural attributes and downstream negative feedback signaling loops that protect it against inhibitors.

Src family
Many human epithelial cancers have increased activity of the c-src and c-yes gene products, suggesting that these activated tyrosine kinases have tumorigenic functions analogous to their highly transforming viral oncogene homologs v-src and v-yes. However, cellular Src and Yes in human tumors lack the mutational and promiscuous attributes of their retroviral homologs and their role in human tumorigenesis remains presumptive and mechanistically undefined. Our laboratory is interested in understanding the functions of Src kinases in human epithelial tumors and the potential of this kinase family as a target for anti-cancer drug development. Our work has focused on a novel substrate of Src kinases that we purified and cloned named Trask. Trask is a transmembrane glycoprotein unrelated to any other genes and is phosphorylated by Src kinases during epithelial cell detachment from matrix. Trask is widely expressed in most epithelial tissues, but its phosphorylation is tightly regulated and restricted to the anchorage deprived state. However, Trask phosphorylation is widely seen in epithelial cancers. Preliminary overexpression and knockdown studies suggest that Trask functions to regulate cell adhesion and cytoskeletal dynamics. Our group is studying the functions of Trask through structure-function studies, engineered cell models, and mouse genetic models.