PIPs, Ubiquitination, and Human Diseases
Many human diseases arise from defects in phosphoinositide (PIP) metabolism, ubiquitination, and Wnt signaling. Phosphoinositides and ubiquitination are major systems that modulate signal transduction in space and time. Jeremy Baskin, Chemistry and Chemical Biology/Weill Institute for Cell and Molecular Biology, and his team of researchers are investigating a cellular mechanism that links these important pathways.
While PIPs’ primary regulatory mechanisms are well characterized, secondary layers of regulation, particularly those regulating crosstalk, have received less attention. The researchers have identified a novel link between PIPs and ubiquitination, mediated by a previously unstudied pleckstrin homology (PH) domain-containing protein.
They discovered that this multi-domain protein forms large assemblies at the plasma membrane via a unique combination of lipid- and protein-binding domains, and it recruits a unique E3 ubiquitin ligase to such structures. This relocalization is accompanied by a decrease in E3 ligase activity toward a major substrate implicated in the Wnt signaling pathway, leading to increases in Wnt signaling. It remains unknown how, mechanistically, lipid binding of the PH domain-containing protein modulates E3 ligase activity, at both the molecular and functional levels.
The researchers will test a novel sequestration model to explain and understand these results. Their long-term research goal is to understand how PIP-sensing proteins link membrane lipid composition to regulate signaling proteins in diverse physiological contexts. Ultimately, understanding how these proteins can read the dynamically changing PIP content of membrane bilayers and use that information to regulate E3 ligase activity will define a new mechanistic framework for regulation of important signaling pathways in health and disease.
NIH Award Number: 1R01GM131101-01