Phosphoinositides (PIPs) are essential lipids that localize in the cytoplasmic leaflet of the biological membranes. By providing a signature lipid interface on the eukaryotic cell membranes, PIPs act as the code of membrane identity. Despite their low cellular abundance, PIPs impart remarkable contributions to essentially all facets of the intra and intercellular signaling processes governing critical physiological outcomes. They do so by interacting with a large array of PIP-binding “reader” proteins (effectors) at membranes to organize and frame downstream signaling entities. Pleckstrin homology (PH) domain-containing proteins represent the 11th most expressed protein family spanning 1% of the entire proteome. Despite being the largest family of such PIP “reader” proteins, only a small number of PH domain-containing proteins are well characterized for their membrane recognition and downstream signaling. This dissertation describes the biomolecular and pathophysiological characterization of a multidomain PH domain-containing protein, PLEKHA4 (Pleckstrin homology domain-containing family A, member 4). PLEKHA4 forms a phase separated signaling hub at PI(4,5)P2-rich clusters of the plasma membrane and recruits the Cullin-3 (CUL3) E3 ubiquitin ligase substrate adaptor Kelch-like protein 12 (KLHL12) to these assemblies. This recruitment decreases CUL3–KLHL12-mediated polyubiquitination of Dishevelled (DVL), a central intermediate in both ß-catenin-dependent and -independent Wnt signaling. I, therefore, establish a novel PLEKHA4 mediated nexus between phosphoinositide signaling at the plasma membrane with ubiquitination and Wnt signaling machineries. Capitalizing on this new signaling axis, I further define the role of PLEKHA4 in melanoma, which despite promising advances in targeted and immunotherapies still accounts for the highest skin cancer mortality. PLEKHA4 knockdown in melanoma cells led to lower Dishevelled levels, attenuated Wnt/ß-catenin signaling, and a block of progression through the G1/S cell cycle transition. In mouse allo/xenograft models, loss of PLEKHA4 attenuated tumor growth in BRAF- and NRAS-mutant melanomas and exhibited an additive effect with the clinically used inhibitor encorafenib in a BRAF-mutant model. This dissertation identifies PLEKHA4, an E3 ubiquitin ligase regulator with both lipid and protein interactors, as a promising drug target for melanoma and clarifies a controversial role for Wnt/ß-catenin signaling in the control of melanoma proliferation.