RF05 | PSUN357 Scaffold Protein IQGAP1 Bridges Proliferative Signaling Between Bile Acids and the Cellular Microenvironment to Mediate Hepatic Cell Proliferation

Abstract

Abstract The cell-cell and cell-extracellular matrix (ECM) communication is central to maintain cellular functions, including proliferation. Scaffold proteins can mediate these communications by binding specific protein effectors of signaling pathways and tethering them into a stable complex. IQ-domain containing GTPase Activating Protein 1 (IQGAP1) is a multi-domain scaffold protein that is involved in cytokinesis, proliferation and apoptosis. Each of the five domains of IQGAP1 bind distinct effector proteins to transduce cellular signals. In the liver, supraphysiological levels of bile acids, a cholesterol metabolite, is linked to the increase in IQGAP1 levels and is positively associated with transcriptional co-activator YAP. However, how bile acids induce expression of IQGAP1 remains unknown. We hypothesize that supraphysiological levels of bile acids act on the cell microenvironment to activate IQGAP1. As bile acids are induced during liver regeneration, we examined and found that Iqgap1 levels are increased. Remarkably this increase in Iqgap1 transcript coincides with that of bile acids after 2/3 partial hepatectomy in mice. In addition, IQGAP1 demonstrated increased localization into puncta at the cell surface in HepG2 cells, seeded on ECM microarrays with higher stiffness indicating mechano-sensing signals can alter IQGAP1 protein levels. We will examine IQGAP1 localization during liver regeneration and investigate if there is a cross talk between ECM stiffness, bile acid and IQGAP1 expression. Using domain deletion constructs, we will also identify the IQGAP1 domain responsible for coordinating the bile acid and cell-ECM communication in the liver. Collectively, these results will help elucidate the IQGAP1-specific cell signaling pathways used in facilitating liver cell proliferation, and test if IQGAP1 scaffold can integrate metabolite cues (bile acids) to communication between liver cells and the cellular microenvironment. Presentation: Saturday, June 11, 2022 1:06 p.m. - 1:11 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.