IQGAP1 in tumorigenesis

Clinical Center

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Abstract

During the fiscal year, we accomplished the following: 1. The Hippo signaling pathway is a master regulator of organ size and tissue homeostasis. Hippo integrates a broad range of cellular signals to regulate numerous processes, such as cell proliferation, differentiation, migration and mechanosensation. We explored the intricate relationship between Pannexin 1 (PANX1) and the Hippo signaling pathway effector, Yes-associated protein (YAP). Analysis of The Cancer Genome Atlas (TCGA) data revealed a significant positive correlation between PANX1 mRNA and core Hippo components, YAP (Yes-associated protein), TAZ, and the Hippo scaffold protein, IQGAP1, in invasive cutaneous melanoma and breast carcinoma. Furthermore, we demonstrated that PANX1 expression is upregulated in invasive melanoma cell lines and is associated with increased YAP protein levels. Our investigations uncovered a previously unrecognized interaction between endogenous PANX1 and the Hippo scaffold protein IQGAP1 in melanoma cells. Moreover, our findings revealed that IQGAP1 exhibits differential expression in melanoma cells and plays a regulatory role in cellular morphology. Functional studies involving PANX1 knockdown provided compelling evidence that PANX1 modulates YAP protein levels and its co-transcriptional activity in both melanoma and breast carcinoma cells. Importantly, our study highlights the potential therapeutic significance of targeting PANX1. Pharmacological inhibition of PANX1 using selective FDA-approved inhibitors or PANX1 knockdown reduced YAP levels in melanoma cells.. Furthermore, Clariom™ S analysis unveiled key genes implicated in cell proliferation, such as neuroglin1 (NRG1), β-galactoside binding protein, galectin-3 (LGALS3), that are affected in PANX1-deficient cells. In summary, our investigation delves into the intricate interplay between PANX1 and YAP in the context of invasive melanoma, offering valuable insights into potential therapeutic strategies for effective treatment. 2. The epithelial Na+ channel (ENaC), by mediating the flow of Na+ ions across biological membranes, plays a key role in the regulation of Na+ and water absorption in several human epithelia. IQGAP1 is a scaffold protein that mediates diverse cellular processes including intracellular signaling and trafficking. The aim of the study was to ascertain whether ENaC interacted with the scaffold protein IQGAP1 and whether IQGAP1 influenced ENaC function. Using immunohistochemistry, we observed that IQGAP1 co-resides with aquaporin 2 in ENaC-expressing principal cells of the distal nephron of mouse kidney. We showed that purified IQGAP1 binds directly to the α-, β-, and γ-subunits of ENaC in vitro. Moreover, we demonstrated that endogenous IQGAP1 co-immunoprecipitates with ENaC subunits from MDCK cell lysates. Functionally, co-expression of IQGAP1 with ENaC in Xenopus oocytes reduces ENaC surface abundance and amiloride-sensitive Na+ transport activity. Together, our data indicate that IQGAP1 binds to ENaC, which likely influences channel trafficking to regulate its cell surface abundance and Na+ transport function. More broadly, these observations suggest new physiological roles for IQGAP1 in Na+ and water absorption across apical epithelial membranes. As ENaC has a fundamental role in regulating blood pressure in people, our data could potentially lead to novel therapeutics for treatment of hypertension.