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 Parkinsons 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.
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