Pleckstrin-2 Promotes Cutaneous Squamous Cell Carcinoma by Recruiting Profilin-1 to the Membrane to Destabilize Cytosolic PTEN

Cutaneous squamous cell carcinoma (cSCC) is a prevalent skin malignancy driven by ultraviolet-induced genomic damage, and advanced disease remains clinically challenging due to limited therapeutic options. Through integrative transcriptomic and functional analyses, we identify Pleckstrin-2 (PLEK2) as a previously unrecognized oncogenic driver in cSCC. PLEK2 is markedly upregulated in patient tumors, cSCC cell lines, and UV-induced mouse models. Genetic perturbation studies demonstrate that PLEK2 promotes proliferation, migration, epithelial–mesenchymal transition, and tumorigenicity. Mechanistically, PLEK2 recruits Profilin-1 (PFN1) to the plasma membrane through its DEP domain, thereby reducing cytosolic PFN1 pool required for PTEN stabilization. This PFN1 sequestration accelerates PTEN polyubiquitination and degradation, thereby sustaining AKT pathway activation. Upstream, we identify ETS2 as a direct transcriptional activator of PLEK2, establishing an ETS2–PLEK2–PFN1–PTEN axis that drives cSCC progression. These findings delineate a signaling pathway regulating PTEN stability and AKT activation, and provide mechanistic insight into cSCC progression.