The cytoskeleton, composed of microfilaments, intermediate filaments, and microtubules, provides the structural basis for cellular functions such as motility and adhesion. Equally crucial, phosphoinositide (PIP_n) signaling is a critical regulator of these processes and other biological activities, though its precise impact on cytoskeletal dynamics has yet to be systematically investigated. This review explores the complex interplay between PIP_n signaling and the cytoskeleton, detailing how PIP_n modulates the dynamics of actin, intermediate filaments, and microtubules to shape cellular behavior. Dysregulation of PIP_n signaling is implicated in various diseases, including cancer, highlighting promising therapeutic opportunities through targeted modulation of these pathways. Future research should aim to elucidate the intricate molecular interactions and broader cellular responses to PIP_n signaling perturbations, particularly in disease contexts, to devise effective strategies for restoring cytoskeletal integrity.

Summary: Phosphoinositide (PIP _n ) messengers are present in non-membranous regions of nuclei where they are assembled into a phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway that is distinct from the cytosolic membrane-localized pathway. In the nuclear pathway, PI kinases/phosphatases bind the p53 tumor suppressor protein (wild-type and mutant) to generate p53-PIP _n complexes (p53-PIP _n signalosome) that activate Akt by a PI3,4,5P ₃ -dependent mechanism in non-membranous regions of the nucleus. This pathway is dependent on a source of nuclear PIP _n s that is poorly characterized. Here we report that a subset of PI transfer proteins (PITPs), which transport PI between membranes to enable membrane-localized PIP _n synthesis, also interact with p53 in the nucleus upon genotoxic stress. Class I PITPs (PITPα/β) specifically supply the PI required for the generation of p53-PIP _n complexes and subsequent signaling in the nucleus. Additionally, the PI 4-kinase PI4KIIα binds to p53 and the PITPs to catalyze the formation of p53-PI4P. p53-PI4P is then sequentially phosphorylated to synthesize p53-PIP _n complexes that regulate p53 stability, nuclear Akt activation and genotoxic stress resistance. In this way, PITPα/β and PI4KIIα bind p53 and collaborate to initiate p53-PIP _n signaling by mechanisms that require PI transfer by PITPα/β and the catalytic activity of PI4KIIα. Moreover, the identification of these critical upstream regulators of p53-PIP _n signaling point to PITPα/β and PI4KIIα as potential therapeutic targets in this pathway for diseases like cancer. In Breif: Phosphatidylinositol transfer proteins and a PI 4-kinase initiate nuclear p53-PIP _n signaling in membrane-free regions.