Andrea Carrano

carrano@salk.edu

Mutations that affect either the enzymatic machinery of the ubiquitin pathway or the ability of a specific substrate to be targeted for ubiquitination can result in the dysregulation of cellular proliferation and other biological processes. Defects in ubiquitin E3 ligases have been implicated in the pathogenesis of several human diseases including Cancer and neurological disorders such as Angelman syndrome and Parkinson’s disease. HECT (homologous to E6AP C-terminus) E3 ligases promote the ubiquitination of proteins that are essential in a variety of cellular events. Because of their central role in the control of diverse signaling pathways, it is not surprising that diseases due to defects in HECT ligase function exist. We have decided to focus our study on a sub-family of HECT ligases containing modules known as WW domains. This sub-family consists of three members, WWP1, WWP2, and Itch. While the functions of WWP1 and WWP2 are still unknown, a mutation in the Itch locus in mice causes pulmonary chronic interstitial inflammation and inflammation of the glandular stomach and skin. Using biochemical, cell biology, and genetic approaches we hope to understand what cellular pathways these E3 ligases are involved in and identify their cellular targets.

Targeting components of the ubiquitin pathways can lead to the development of new therapeutic agents. Because of the wide-ranging role of this pathway in many cellular processes, it may be difficult to limit the negative effects of inhibitors that target the general ubiquitination machinery. However, inhibitors of ubiquitin ligases will more specifically block distinct selected cellular processes. Our overall goal is to explore the potential of HECT E3 ligases as novel therapeutic targets in cancer or other diseases.