Thursday, November 21, 2024
11/21/2024
Our lab studies how transmembrane proteins signal from the cell's external environment to its interior during animal development and adulthood, how dysregulation of transmembrane signaling leads to disease, and how to correct pathological transmembrane signaling via novel mechanism-inspired therapeutic strategies. We focus on the Hedgehog (Hh) pathway, a fundamental signaling cascade that specifies the development of nearly every vertebrate organ and ensures homeostasis during adulthood. Hh also serves as a leading model for signal transduction within the primary cilium, a tiny antenna-shaped protrusion found on nearly every cell in the body that is critical for G protein-coupled receptor (GPCR) cascades in many physiological systems. While the importance of Hh signaling in health and disease is clear, the biochemical mechanisms underlying the central steps in this cascade are surprisingly mysterious. Our MIRA program focuses on three central problems in Hh and GPCR signaling: 1) How are Hh signals received and deciphered at the cell surface? 2) How are Hh signals transmitted intracellularly? 3) Why must many GPCRs localize to the cilium to perform their biological functions? Our seminal contributions from the work of our first MIRA include: 1) Defining the biochemical and structural mechanism of activation for SMOOTHENED (SMO), an atypical GPCR and the key transducer of Hh signals at the ciliary membrane. We found that SMO is activated by cholesterol, which binds to a site deep within the SMO membrane-spanning domain; and 2) Demonstrating that SMO signals intracellularly via a mechanism unprecedented in GPCR biology: SMO directly binds the protein kinase A (PKA) catalytic subunit and physically blocks its enzymatic activity. These discoveries have generated new principles regarding how cholesterol can serve as a GPCR’s key activating “switch”, and how GPCRs can directly regulate the activity of kinases. The next phase of our MIRA builds on this foundation, tackling a number of the outstanding questions in the field. We will learn how SMO is regulated by the Hh receptor and putative sterol transporter PTCH1, test our mechanistic model for SMO activity using in vivo Hh signal transduction systems, and learn how SMO-PKA signaling is regulated by lipids proteins, post-translational modifications, and pathway deactivation mechanisms. Finally, we will embark on a new research direction, using the concepts and tools from our Hh studies to test roles for cholesterol and phosphorylation codes in the operation of ciliary GPCRs. Together, these investigations will advance our understanding of the signal transduction mechanisms underlying Hh and other ciliary GPCR cascades, with broad implications for development, physiology, and disease. These studies will also enable the generation of diagnostic and therapeutic tools for a range of devastating disorders, including congenital defects, malignancies, and dysfunction of the nervous, cardiovascular, and musculoskeletal systems.
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).
