Shafi Kuchay, PhD
Assistant Professor
Department of Biochemistry and Molecular Genetics
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Major Interests Heading link
Cellular membranes serve as dynamic hubs for the assembly of many multi-protein complexes that play important roles in maintaining healthy cellular functions. Dysregulation of membrane proteins and signaling pathways they are involved in leads to disease, including cancer. Therefore, cells employ different strategies to keep membrane proteins in check, including ways to regulate their abundance. One such system that controls the turnover of numerous regulatory proteins to swiftly and specifically regulate cellular networks with precision is the ubiquitin-proteasome system (UPS). We employ systematic approaches to investigate the regulation of membrane protein abundance by the UPS.
Although UPS in general is well studied, its role in regulating membrane proteins remains somewhat enigmatic. To offer important new insights and illuminate this understudied area of biology, we are focusing on identifying ubiquitin regulated pathways that operate at cellular membranes as well as elucidating the underlying molecular mechanisms involved. We are particularly interested in uncovering functional involvement in disease (cancer and other disorders). Our current laboratory research involves two complementary areas:
(1) Systematic functional characterization of membrane bound E3 ubiquitin ligases, enzymes that serve to recognize and recruit target protein substrates and mark them for proteasomal destruction by catalyzing transfer of ubiquitin onto them. For example, we are investigating FBXL2, an E3 ligase complex that regulates signaling networks operating from membrane compartments.
(2) Systematic functional characterization of post-translational modifications involved in regulation of membrane bound E3 ubiquitin ligases. For example, we are investigating a new prenyltransferase that we named GGTase3 involved in prenylation, a lipid modification, of FBXL2 for targeting to membranes.
Honors and Awards Heading link
Selected Publications
1. Kuchay S., Wang H., Homer H., Marzio A., Jain K., Homer H., Fehrenbacher N., Philips MR., Zheng N., and Pagano M. GGTase3 is a Newly Identified Geranylgeranyltransferase Targeting a Ubiquitin Ligase. Nat Struct Mol Biol 26: 628-636, 2019. [Editors choice Highlight] [News & Thoughts]
2. Kuchay S., et al. NS5A promotes constitutive degradation of IP3R3 to counteract apoptosis induced by hepatitis C virus. Cell Reports 25, 833–840, 2018.
3. Kuchay S., et al. PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumor growth. Nature 546:554-558,2017. [News & Views] [ News & Thoughts]
4. Kuchay S., et al. FBXL2- and PTPL1-mediated and PTPL1- mediated degradation of p85β controls PI3K activity. Nature Cell Biol 15: 472-480, 2013.
Education
Postdoctoral, HHMI/NYU School of Medicine (PAGANO LAB); PhD, University of Illinois at Chicago.