Saturday, June 14, 2025
6/14/2025
Novel Regulation of Receptor Tyrosine Kinases by ASM (Acidic Sphingomyelinase) - Project Summary We propose that ASM (acid sphingomylinase) is a critical regulator of RTKs (receptor tyrosine kinases), and that ASM can serve as a novel therapeutic target for various cancers, including gliomablastoma multiforme (GBM). Also as loss of function of ASM may cause the severe neuron degeneration phenotype in the rare familial Niemann Pick Disease, type A, our studies may provide molecular insights into this disease. The plasma membrane is a lipid bilayer composed primarily of phospholipids, as well as sphingomyelins, cholesterol, glycosphingolipids and other less abundant lipid molecules such as ceremides. The composition of the plasma membrane lipids is dynamically regulated and undergoes rapid exchanges with intracellular organelles such as Golgi, endosomes and lysosomes through secretion, exocytosis and endocytosis. For many transmembrane and membrane-associated proteins, including RTKs, specific interaction with various lipid molecules in the plasma membrane is an integral part of regulation to maintain their protein structure and function. However, the mechanisms by which specific lipid molecules regulate the dynamic activities of RTKs and other transmembrane or membrane-associated proteins are not well characterized. In this application, we propose to investigate the roles of ASM (also called SMPD1) in regulating the RTK-mediated cell signaling processes. We have recently found that the levels of ASM (acidic sphinomyelinase) are highly elevated in GBM and our studies reveal that ASM is required for the activation of multiple RTKs. ASM is an enzyme involved in sphingolipid metabolism that hydrolyzes sphingomyelin to produce ceramide. Ceramide, with a biophysical property of self-association, is involved in establishing a lipid microenvironment that promotes protein-protein interactions. Mutations of human ASM gene cause Niemman-Pick disease, type A, an inherited disease that induces massive loss of Purkinje neurons in the cerebellum and patients usually die by 2 or 3 years of ages, but the underlying molecular mechanism of ASM deficiency for the disease remains unresolved. In this application, we will investigate the mechanism by which ASM regulates the RTK signaling pathway, by following specific aims: Specific aim 1: To determine how ASM regulates the activation RTK receptor proteins. Specific aim 2: To investigate the involvement of ASM sphinomyelinase activity in RTK signaling. Specific aim 3: To examine whether ASM regulates RTK signaling at multiple levels. As co-activation of RTKs is critically important in GBM and in a multitude of human disorders and diseases, elucidation of this new regulatory mechanism may provide novel targets for prevention and therapeutic treatment. Our studies should also provide molecular underpinning how loss-of-function of ASM causes neuron degeneration in the human diseases such as Niemman-Pick disease, type A.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).