{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPIP5K1A is a central mediator of plasma membrane dynamics by catalyzing the local synthesis of phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P₂), a lipid that orchestrates actin remodeling and membrane trafficking. In response to growth factors and immune receptor stimulation, PIP5K1A becomes locally activated—promoting membrane ruffling, invadopodia formation, integrin‐dependent Rac1 translocation, and efficient receptor internalization. It thereby facilitates processes ranging from cell motility and adhesion to viral entry and assembly, as seen with HIV‐1, while also contributing to protection against apoptotic stimuli and supporting natural killer cell cytotoxicity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its membrane‐proximal functions, PIP5K1A plays critical roles in oncogenic signaling and cellular differentiation. By partnering with scaffold proteins such as IQGAP1, it channels its PI(4,5)P₂ product toward PI3K–Akt activation—a pathway that fuels cell growth and survival in various cancers, including triple–negative breast cancer and prostate cancer—and even modulates chemotherapeutic resistance via circRNA forms. Moreover, its physical interaction with oncogenic KRAS specifically amplifies MAPK signaling. In epithelial cells, PIP5K1A is recruited to adhesion complexes (via the E–cadherin–catenin module and PP1-mediated dephosphorylation) to drive calcium–induced differentiation, and in T lymphocytes, it is essential for CD28 costimulatory signals leading to cytokine gene expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent evidence has also uncovered unexpected nuclear and post–transcriptional roles for PIP5K1A. A distinct nuclear pool of the enzyme undergoes SUMOylation and associates with components of chromatin–based silencing complexes at rDNA loci, suggesting a role in regulating gene expression. In parallel, nuclear PIP5K1A interacts (in a kinase–independent manner) with the RNA export factor XPO5 to control the biogenesis of key microRNAs such as let–7, and it facilitates the translation of inflammatory cytokines like IL–17A in T helper 17 cells through interactions with RNA–binding proteins."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Renee L Doughman, Ari J Firestone, Michelle L Wojtasiak, et al. 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