Lipid regulation of cellular signaling and protein-protein interactions Eukaryotic cells can be regarded as a vast, extensively compartmentalized and hierarchic protein- protein interaction (PPI) network. Characterizing PPI is therefore a crucial step in gaining an understanding of how cells function. PPI has also emerged as an attractive target space for drug development since PPI regulates numerous cellular processes, such as cell signaling. Despite the wealth of PPI data, however, the mechanisms by which complex cellular PPIs are coordinated and regulated with high spatiotemporal specificity are still poorly understood. This makes it difficult to understand the mechanisms of cell regulation on a systems level and also hampers development of specific drugs targeting PPI. Many PPI networks and protein complexes are formed on or near the cell membranes, the plasma membrane in particular. However, direct involvement of membrane lipids in coordination and modulation of PPI has not been explored. We have recently made breakthroughs in this line of research and revolutionized the PPI research by establishing that lipids directly and specifically regulate cellular PPI. This important new discovery as well as our innovative in situ quantitative lipid imaging technology give us a unique and unparalleled opportunity to systematically investigate how various lipids modulate PPI. We will study the mechanisms by which various lipids, including cholesterol and phosphoinositides, regulate a wide variety of cellular processes by spatiotemporally coordinating and modulating PPI through their specific interaction with protein interaction domains, including PDZ and SH2 domains. We will also develop new small molecule modulators of lipid-dependent PPI as drug candidates for various human diseases, including cancer. Given the general and fundamental importance of PPI, our pioneering, innovative research should have high potential impact on broad areas of biology and medicine.

Public Health Relevance

Protein-protein interaction (PPI) regulates numerous cellular processes, such as cell signaling, and many human diseases, including cancer, are caused by dysregulation of PPI. PPI has thus emerged as an attractive target space for drug development. Despite the wealth of PPI data, however, the mechanisms by which complex cellular PPIs are exquisitely coordinated and regulated are still poorly understood, which hampers development of specific drugs targeting PPI. We have recently discovered that membrane lipids directly and specifically regulate cellular PPI. This important new discovery not only provides new insight into to how cellular PPI is regulated with high spatiotemporal specificity but also opens exciting new avenues of developing drugs targeting lipid-protein binding interfaces. Given the general and fundamental importance of PPI, our pioneering, innovative research should have high potential impact on broad areas of biology and medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM122530-01
Application #
9276835
Study Section
Special Emphasis Panel (ZGM1-TRN-7 (MR))
Program Officer
Ainsztein, Alexandra M
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$533,775
Indirect Cost
$191,128
Name
University of Illinois at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Wood, Megan N; Ishiyama, Noboru; Singaram, Indira et al. (2017) ?-Catenin homodimers are recruited to phosphoinositide-activated membranes to promote adhesion. J Cell Biol 216:3767-3783