The nuclear phosphoinositide-p53 signalosome in the regulation of cell motility

Abstract

Dysregulation of p53 and phosphoinositide (PIP_n) signaling are both key drivers of oncogenesis and metastasis. Our recent findings reveal a previously unrecognized interaction between these pathways, converging in the nucleus to form a PIP_n-p53 signalosome that modulates nuclear AKT activation and downstream signaling, thereby influencing cancer cell survival and motility. This review examines recent insights into nuclear PIP_n signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIP_ns interact with p53 to form signalosomes that affect cell motility. We emphasize the critical role of PIP_ns in stabilizing p53 and activating de novo nuclear AKT signaling, which subsequently modulates key motility-related pathways. Understanding the unique operation and function of the PIP_n-p53 signalosome in nuclear phosphatidylinositol 3-kinase (PI3K)-AKT activation offers novel therapeutic strategies for controlling cancer metastasis by targeting pertinent interactions and events.

Keywords

phosphoinositide / p53 / signalosome / nucleus / cell motility

References

[1] Abraham AG , O’Neill E . PI3K/Akt-mediated regulation of p53 in cancer. Biochem Soc Trans 2014; 42: 798- 803.

[2] Agarwal ML , Taylor WR , Chernov MV et al. The p53 network. J Biol Chem 1998; 273: 1- 4.

[3] Ahmed NN , Franke TF , Bellacosa A et al. The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene 1993; 8: 1957- 1963.

[4] Alli-Balogun GO , Gewinner CA , Jacobs R et al. Phosphatidylinositol 4-kinase IIβ negatively regulates invadopodia formation and suppresses an invasive cellular phenotype. Mol Biol Cell 2016; 27: 4033- 4042.

[5] Araki K , Ebata T , Guo AK et al. p53 regulates cytoskeleton remodeling to suppress tumor progression. Cell Mol Life Sci 2015; 72: 4077- 4094.

[6] Ashlin TG , Blunsom NJ , Cockcroft S . Courier service for phosphatidylinositol: PITPs deliver on demand. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866: 158985.

[7] Balla T . Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol Rev 2013; 93: 1019- 1137.

[8] Balla A , Balla T . Phosphatidylinositol 4-kinases: old enzymes with emerging functions. Trends Cell Biol 2006; 16: 351- 361.

[9] Banfic H , Visnjic D , Mise N et al. Epidermal growth factor stimulates translocation of the class II phosphoinositide 3-kinase PI3K-C2β to the nucleus. Biochem J 2009; 422: 53- 60.

[10] Barlow CA , Laishram RS , Anderson RA . Nuclear phosphoinositides: a signaling enigma wrapped in a compartmental conundrum. Trends Cell Biol 2010; 20: 25- 35.

[11] Blind RD , Suzawa M , Ingraham HA . Direct modification and activation of a nuclear receptor-PIP2 complex by the inositol lipid kinase IPMK. Sci Signal 2012; 5: ra44.

[12] Blunsom NJ , Cockcroft S . CDP-diacylglycerol synthases(CDS): gateway to phosphatidylinositol and cardiolipin synthesis. Front Cell Dev Biol 2020a; 8: 63.

[13] Blunsom NJ , Cockcroft S . Phosphatidylinositol synthesis at the endoplasmic reticulum. Biochim Biophys Acta Mol Cell Biol Lipids 2020b; 1865: 158471.

[14] Boronenkov IV , Loijens JC , Umeda M et al. Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing pre-mRNA processing factors. Mol Biol Cell 1998; 9: 3547- 3560.

[15] Bunce MW , Boronenkov IV , Anderson RA . Coordinated activation of the nuclear ubiquitin ligase Cul3-SPOP by the generation of phosphatidylinositol 5-phosphate. J Biol Chem 2008; 283: 8678- 8686.

[16] Bura A , Čabrijan S , Đurić I et al. A plethora of functions condensed into tiny phospholipids: the story of PI4P and PI (4,5)P₂. Cells 2023; 12: 1411.

[17] Butera A , Amelio I . Deciphering the significance of p53 mutant proteins. Trends Cell Biol 2025; 35: 258- 268.

[18] Carrillo ND , Chen M , Wen T et al. Lipid transfer proteins and a PI 4-kinase initiate nuclear phosphoinositide signaling. BioRxiv 2025: 2023.05.08.539894.

[19] Chakrabarti R , Sanyal S , Ghosh A et al. Phosphatidylinositol-4-phosphate 5-kinase 1α modulates ribosomal RNA gene silencing through its interaction with histone H3 Lysine 9 trimethylation and heterochromatin protein HP1-α. J Biol Chem 2015; 290: 20893- 20903.

[20] Chang CJ , Chao CH , Xia W et al. p53 regulates epithelialmesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 2011; 13: 317- 323.

[21] Charest PG , Firtel RA . Big roles for small GTPases in the control of directed cell movement. Biochem J 2007; 401: 377- 390.

[22] Chen M , Choi S , Jung O et al. The specificity of EGF-stimulated IQGAP1 scaffold towards the PI3K-Akt pathway is defined by the IQ3 motif. Sci Rep 2019; 9: 9126.

[23] Chen M , Wen T , Horn HT et al. The nuclear phosphoinositide response to stress. Cell Cycle 2020; 19: 268- 289.

[24] Chen M , Horn HT , Wen T et al. Assessing in situ phosphoinositide-protein interactions through fluorescence proximity ligation assay in cultured cells. Methods Mol Biol 2021; 2251: 133- 142.

[25] Chen M , Choi S , Wen T et al. A p53-phosphoinositide signalosome regulates nuclear AKT activation. Nat Cell Biol 2022; 24: 1099- 1113.

[26] Chen C , Chen M , Wen T et al. Regulation of NRF2 by Phosphoinositides and small heat shock proteins. bioRxiv 2024:2023.10.26.564194.

[27] Cheng GZ , Zhang W , Wang L-H . Regulation of cancer cell survival, migration, and invasion by Twist: AKT2 comes to interplay. Cancer Res 2008; 68: 957- 960.

[28] Chibaya L , Karim B , Zhang H et al. Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis. Proc Natl Acad Sci USA 2021; 118: e2003193118.

[29] Choi BH , Chen Y , Dai W . Chromatin PTEN is involved in DNA damage response partly through regulating Rad52 sumoylation. Cell Cycle 2013; 12: 3442- 3447.

[30] Choi S , Hedman AC , Sayedyahossein S et al. Agoniststimulated phosphatidylinositol-3,4,5-trisphosphate generation by scaffolded phosphoinositide kinases. Nat Cell Biol 2016; 18: 1324- 1335.

[31] Choi S , Chen M , Cryns VL et al. A nuclear phosphoinositide kinase complex regulates p53. Nat Cell Biol 2019; 21: 462- 475.

[32] Cingolani LA , Goda Y . Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci 2008; 9: 344- 356.

[33] Cocco L , Gilmour RS , Ognibene A et al. Synthesis of polyphos-phoinositides in nuclei of Friend cells. Evidence for polyphos-phoinositide metabolism inside the nucleus which changes with cell differentiation. Biochem J 1987; 248: 765- 770.

[34] Cocco L , Rubbini S , Manzoli L et al. Inositides in the nucleus:presence and characterisation of the isozymes of phospholipase β family in NIH 3T3 cells. Biochim Biophys Acta 1999; 1438: 295- 299.

[35] Coutts AS , Weston L , La Thangue NB . A transcription co-factor integrates cell adhesion and motility with the p53 response. Proc Natl Acad Sci USA 2009; 106: 19872- 19877.

[36] de Graaf P , Klapisz EE , Schulz TK et al. Nuclear localization of phosphatidylinositol 4-kinase β. J Cell Sci 2002; 115: 1769- 1775.

[37] Deleris P , Bacqueville D , Gayral S et al. SHIP-2 and PTEN are expressed and active in vascular smooth muscle cell nuclei, but only SHIP-2 is associated with nuclear speckles. J Biol Chem 2003; 278: 38884- 38891.

[38] de Vries A , Flores ER , Miranda B et al. Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. Proc Natl Acad Sci USA 2002; 99: 2948- 2953.

[39] Didichenko SA , Thelen M . Phosphatidylinositol 3-kinase c2α contains a nuclear localization sequence and associates with nuclear speckles. J Biol Chem 2001; 276: 48135- 48142.

[40] Ehm P , Nalaskowski MM , Wundenberg T et al. The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies. Nucleus 2015; 6: 154- 164.

[41] Elis W , Triantafellow E , Wolters NM et al. Down-regulation of class II phosphoinositide 3-kinase alpha expression below a critical threshold induces apoptotic cell death. Mol Cancer Res 2008; 6: 614- 623.

[42] Elong Edimo W , Derua R , Janssens V et al. Evidence of SHIP2 Ser132 phosphorylation, its nuclear localization and stability. Biochem J 2011; 439: 391- 401.

[43] Enomoto A , Murakami H , Asai N et al. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell 2005; 9: 389- 402.

[44] Faenza I , Fiume R , Piazzi M et al. Nuclear inositide specific phospholipase C signalling - interactions and activity. FEBS J 2013; 280: 6311- 6321.

[45] Gadéa G , Lapasset L , Gauthier-Rouvière C et al. Regulation of Cdc42-mediated morphological effects: a novel function for p53. EMBO J 2002; 21: 2373- 2382.

[46] Gadea G , de Toledo M , Anguille C et al. Loss of p53 promotes RhoA-ROCK-dependent cell migration and invasion in 3D matrices. J Cell Biol 2007; 178: 23- 30.

[47] Gonzalez E , McGraw TE . The Akt kinases: isoform specificity in metabolism and cancer. Cell cycle 2009; 8: 2502- 2508.

[48] Govindarajan B , Sbrissa D , Pressprich M et al. Adaptor proteins mediate CXCR4 and PI4KA crosstalk in prostate cancer cells and the significance of PI4KA in bone tumor growth. Sci Rep 2023; 13: 20634.

[49] Gozani O , Karuman P , Jones DR et al. The PHD Finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor. Cell 2003; 114: 99- 111.

[50] Gozzelino L , De Santis MC , Gulluni F et al. PI(3,4)P2 signaling in cancer and metabolism. Front Oncol 2020; 10: 360.

[51] Guo F , Gao Y , Wang L et al. p19Arf-p53 tumor suppressor pathway regulates cell motility by suppression of phosphoinositide 3-kinase and Rac1 GTPase activities. J Biol Chem 2003; 278: 14414- 14419.

[52] Hao Y , He B , Wu L et al. Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer. Nat Commun 2022; 13: 1974.

[53] Hassin O , Oren M . Drugging p53 in cancer: one protein, many targets. Nat Rev Drug Discovery 2023; 22: 127- 144.

[54] Hollstein M , Sidransky D , Vogelstein B et al. p53 mutations in human cancers. Science 1991; 253: 49- 53.

[55] Hou X , Chen Y , Carrillo ND et al. Phosphoinositide signaling at the cytoskeleton in the regulation of cell dynamics. Cell Death Dis 2025a; 16: 296.

[56] Hou X , Ren C , Jin J et al. Phosphoinositide signalling in cell motility and adhesion. Nat Cell Biol 2025b; 27: 736- 748.

[57] Hsuan J , Cockcroft S . The PITP family of phosphatidylinositol transfer proteins. Genome Biol 2001; 2: REVIEWS3011.

[58] Huang Y , Jeong JS , Okamura J et al. Global tumor protein p53/p63 interactome: making a case for cisplatin chemoresistance. Cell Cycle 2012; 11: 2367- 2379.

[59] Isaji T , Im S , Kameyama A et al. A complex between phosphatidylinositol 4-kinase IIα and integrin α3β1 is required for N-glycan sialylation in cancer cells. J Biol Chem 2019; 294: 4425- 4436.

[60] Jean S , Kiger AA . Classes of phosphoinositide 3-kinases at a glance. J Cell Sci 2014; 127: 923- 928.

[61] Jung O , Baek M-j , Wooldrik C et al. Nuclear phosphoinositide signaling promotes YAP/TAZ-TEAD transcriptional activity in breast cancer. EMBO J 2024; 43: 1740- 1769.

[62] Kakuk A , Friedlander E , Vereb G et al. Nucleolar localization of phosphatidylinositol 4-kinase PI4K230 in various mammalian cells. Cytometry A 2006; 69: 1174- 1183.

[63] Kakuk A , Friedlander E , Vereb G et al. Nuclear and nucleolar localization signals and their targeting function in phosphatidylinositol 4-kinase PI4K230. Exp Cell Res 2008; 314: 2376- 2388.

[64] Kandoth C , McLellan MD , Vandin F et al. Mutational landscape and significance across 12 major cancer types. Nature 2013; 502: 333- 339.

[65] Karlsson T , Altankhuyag A , Dobrovolska O et al. A polybasic motif in ErbB3-binding protein 1 (EBP1) has key functions in nucleolar localization and polyphos-phoinositide interaction. Biochem J 2016; 473: 2033- 2047.

[66] Ke M , Zhu H , Lin Y et al. Actin-related protein 2/3 complex subunit 1B promotes ovarian cancer progression by regulating the AKT/PI3K/mTOR signaling pathway. J Transl Int Med 2024; 12: 406- 423.

[67] Kennedy MC , Lowe SW . Mutant p53: it’s not all one and the same. Cell Death Differ 2022; 29: 983- 987.

[68] Kouchi Z , Fujiwara Y , Yamaguchi H et al. Phosphatidylinositol 5-phosphate 4-kinase type II beta is required for vitamin D receptor-dependent E-cadherin expression in SW480 cells. Biochem Biophys Res Commun 2011; 408: 523- 529.

[69] Kruse J-P , Gu W . Modes of p53 Regulation. Cell 2009; 137: 609- 622.

[70] Kubbutat MH , Jones SN , Vousden KH . Regulation of p53 stability by Mdm2. Nature 1997; 387: 299- 303.

[71] Kumar A , Redondo-Munoz J , Perez-Garcia V et al. Nuclear but not cytosolic phosphoinositide 3-kinase beta has an essential function in cell survival. Mol Cell Biol 2011; 31: 2122- 2133.

[72] Kunrath-Lima M , de Miranda MC , Ferreira ADF et al. Phospholipase C delta 4 (PLCδ4) is a nuclear protein involved in cell proliferation and senescence in mesenchymal stromal stem cells. Cell Signal 2018; 49: 59- 67.

[73] Langerød A , Zhao H , Borgan O et al. TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res 2007; 9: R30.

[74] Lattanzio R , Iezzi M , Sala G et al. PLC-gamma-1 phosphorylation status is prognostic of metastatic risk in patients with early-stage Luminal-A and -B breast cancer subtypes. BMC Cancer 2019; 19: 747.

[75] Lee SB , Xuan Nguyen TL , Choi JW et al. Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival. Proc Natl Acad Sci USA 2008; 105: 16584- 16589.

[76] Li Y , Luan C . PLCE1 promotes the invasion and migration of esophageal cancer cells by up-regulating the PKCα/NF-κB pathway. Yonsei Med J 2018; 59: 1159- 1165.

[77] Li G , Nelsen C , Hendrickson EA . Ku86 is essential in human somatic cells. Proc Natl Acad Sci USA 2002; 99: 832- 837.

[78] Li P , Wang D , Li H et al. Identification of nucleolus-localized PTEN and its function in regulating ribosome biogenesis. Mol Biol Rep 2014; 41: 6383- 6390.

[79] Li J , Gao Z , Zhao D et al. PI-273, a substrate-competitive, specific small-molecule inhibitor of PI4KIIα, inhibits the growth of breast cancer cells. Cancer Res 2017; 77: 6253- 6266.

[80] Manning BD , Toker A . AKT/PKB signaling: navigating the network. Cell 2017; 169: 381- 405.

[81] Mantovani F , Collavin L , Del Sal G . Mutant p53 as a guardian of the cancer cell. Cell Death Differ 2019; 26: 199- 212.

[82] Manzoli FA , Maraldi NM , Cocco L et al. Chromatin phospholipids in normal and chronic lymphocytic leukemia lymphocytes. Cancer Res 1977; 37: 843- 849.

[83] Marques M , Kumar A , Poveda AM et al. Specific function of phosphoinositide 3-kinase beta in the control of DNA replication. Proc Natl Acad Sci USA 2009; 106: 7525- 7530.

[84] Martelli AM , Tabellini G , Bressanin D et al. The emerging multiple roles of nuclear Akt. Biochim Biophys Acta 2012; 1823: 2168- 2178.

[85] May P , May E . Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene 1999; 18: 7621- 7636.

[86] Mazloumi Gavgani F , Smith Arnesen V , Jacobsen RG et al. Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer. Int J Mol Sci 2018; 19: 3931.

[87] Meier R , Alessi DR , Cron P et al. Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta. J Biol Chem 1997; 272: 30491- 30497.

[88] Mellman DL , Gonzales ML , Song C et al. A PtdIns4, 5P2-regulated nuclear poly (A) polymerase controls expression of select mRNAs. Nature 2008; 451: 1013- 1017.

[89] Merino-Casallo F , Gomez-Benito MJ , Hervas-Raluy S et al. Unravelling cell migration: defining movement from the cell surface. Cell Adh Migr 2022; 16: 25- 64.

[90] Meza-Sosa KF , Miao R , Navarro F et al. SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage. Mol Cell 2022; 82: 785- 802.e10.

[91] Mizuarai S , Yamanaka K , Kotani H . Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells. Cancer Res 2006; 66: 6319- 6326.

[92] Morrow AA , Alipour MA , Bridges D et al. The lipid kinase PI4KIIIβ is highly expressed in breast tumors and activates Akt in cooperation with Rab11a. Mol Cancer Res 2014; 12: 1492- 1508.

[93] Muller PA , Vousden KH , Norman JC . p53 and its mutants in tumor cell migration and invasion. J Cell Biol 2011; 192: 209- 218.

[94] Neri LM , Bortul R , Borgatti P et al. Proliferating or differentiating stimuli act on different lipid-dependent signaling pathways in nuclei of human leukemia cells. Mol Biol Cell 2002; 13: 947- 964.

[95] Ogawara Y , Kishishita S , Obata T et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 2002; 277: 21843- 21850.

[96] Okazaki R . Role of p53 in regulating radiation responses. Life(Basel, Switzerland) 2022; 12: 1099.

[97] Olivier M , Hollstein M , Hainaut P . TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010; 2: a001008.

[98] Oren M , Prives C . p53: a tale of complexity and context. Cell 2024; 187: 1569- 1573.

[99] Owusu Obeng E , Rusciano I , Marvi MV et al. Phosphoinositidedependent signaling in cancer: a focus on phospholipase C isozymes. Int J Mol Sci 2020; 21: 2581.

[100] Palmieri M , Catimel B , Mouradov D et al. PI3Kα translocation mediates nuclear PtdIns(3,4,5)P3 effector signaling in colorectal cancer. Mol Cell Proteomics 2023; 22: 100529.

[101] Pedicone C , Meyer ST , Chisholm JD et al. Targeting SHIP1 and SHIP2 in cancer. Cancers (Basel) 2021; 13: 890.

[102] Posor Y , Jang W , Haucke V . Phosphoinositides as membrane organizers. Nat Rev Mol Cell Biol 2022; 23: 797- 816.

[103] Razmara M , Heldin CH , Lennartsson J . Platelet-derived growth factor-induced Akt phosphorylation requires mTOR/Rictor and phospholipase C-γ1, whereas S6 phosphorylation depends on mTOR/Raptor and phospholipase D. Cell Commun Signal 2013; 11: 3.

[104] Ren C , Carrillo ND , Cryns VL et al. Environmental pollutants and phosphoinositide signaling in autoimmunity. J Hazard Mater 2024; 465: 133080.

[105] Rose HG , Frenster JH . Composition and metabolism of lipids within repressed and active chromatin of interphase lymphocytes. Biochim Biophys Acta 1965; 106: 577- 591.

[106] Russo A , Okur MN , Bosland M et al. Phosphatidylinositol 3-kinase, class 2 beta (PI3KC2β) isoform contributes to neuroblastoma tumorigenesis. Cancer Lett 2015; 359: 262- 268.

[107] Saji M , Vasko V , Kada F et al. Akt1 contains a functional leucine-rich nuclear export sequence. Biochem Biophys Res Commun 2005; 332: 167- 173.

[108] Sale E , Sale G . Protein kinase B: signalling roles and therapeutic targeting. Cell Mol Life Sci 2008; 65: 113- 127.

[109] Sarker D , Ang JE , Baird R et al. First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2015; 21: 77- 86.

[110] Sbrissa D , Semaan L , Govindarajan B et al. A novel cross-talk between CXCR4 and PI4KIIIα in prostate cancer cells. Oncogene 2019; 38: 332- 344.

[111] Schill NJ , Anderson RA . Two novel phosphatidylinositol-4-phosphate 5-kinase type Igamma splice variants expressed in human cells display distinctive cellular targeting. Biochem J 2009; 422: 473- 482.

[112] Seok YM , Azam MA , Okamoto Y et al. Enhanced Ca²⁺-dependent activation of phosphoinositide 3-kinase class IIα isoform-Rho axis in blood vessels of spontaneously hypertensive rats. Hypertension 2010; 56: 934- 941.

[113] Shen WH , Balajee AS , Wang J et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 2007; 128: 157- 170.

[114] Sigalotti L , Covre A , Fratta E et al. Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies. J Transl Med 2010; 8: 1- 22.

[115] Sindić A , Aleksandrova A , Fields AP et al. Presence and activation of nuclear phosphoinositide 3-kinase C2β during compensatory liver growth. J Biol Chem 2001; 276: 17754- 17761.

[116] Singh B , Reddy PG , Goberdhan A et al. p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas. Genes Dev 2002; 16: 984- 993.

[117] Sinkala M . Mutational landscape of cancer-driver genes across human cancers. Sci Rep 2023; 13: 12742.

[118] Smith CD , Wells W . Phosphorylation of rat liver nuclear envelopes. II. Characterization of in vitro lipid phosphorylation. J Biol Chem 1983; 258: 9368- 9373.

[119] Sone Y , Ito M , Shirakawa H et al. Nuclear translocation of phospholipase C-zeta, an egg-activating factor, during early embryonic development. Biochem Biophys Res Commun 2005; 330: 690- 694.

[120] Song R , Tian K , Wang W et al. P53 suppresses cell proliferation, metastasis, and angiogenesis of osteosarcoma through inhibition of the PI3K/AKT/mTOR pathway. International Journal of Surgery (London, England) 2015; 20: 80- 87.

[121] Srinivasan S , Wang F , Glavas S et al. Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis. J Cell Biol 2003; 160: 375- 385.

[122] Stallings JD , Tall EG , Pentyala S et al. Nuclear translocation of phospholipase C-δ₁ is linked to the cell cycle and nuclear phosphatidylinositol 4,5-bisphosphate. J Biol Chem 2005; 280: 22060- 22069.

[123] Stijf-Bultsma Y , Sommer L , Tauber M et al. The basal transcription complex component TAF3 transduces changes in nuclear phosphoinositides into transcriptional output. Mol Cell 2015; 58: 453- 467.

[124] Stuelten CH , Parent CA , Montell DJ . Cell motility in cancer invasion and metastasis: insights from simple model organisms. Nat Rev Cancer 2018; 18: 296- 312.

[125] Sun Y , Turbin DA , Ling K et al. Type I gamma phosphatidylinositol phosphate kinase modulates invasion and proliferation and its expression correlates with poor prognosis in breast cancer. Breast Cancer Res 2010; 12: R6.

[126] Sun Y , Isaji T , Oyama Y et al. Focal-adhesion kinase regulates the sialylation of N-glycans via the PI4KIIα-PI4P pathway. J Biol Chem 2023; 299: 105051.

[127] Szivak I , Lamb N , Heilmeyer LM . Subcellular localization and structural function of endogenous phosphorylated phosphatidylinositol 4-kinase (PI4K92). J Biol Chem 2006; 281: 16740- 16749.

[128] Sztacho M , Sobol M , Balaban C et al. Nuclear phosphoinositides and phase separation: important players in nuclear compartmentalization. Advances in Biological Regulation 2019; 71: 111- 117.

[129] Tabellini G , Bortul R , Santi S et al. Diacylglycerol kinase-theta is localized in the speckle domains of the nucleus. Exp Cell Res 2003; 287: 143- 154.

[130] Tan X , Banerjee P , Pham EA et al. PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma. Sci Transl Med 2020; 12: eaax3772.

[131] Tanaka K , Horiguchi K , Yoshida T et al. Evidence that a phosphatidylinositol 3,4,5-trisphosphate-binding protein can function in nucleus. J Biol Chem 1999; 274: 3919- 3922.

[132] Thapa N , Chen M , Horn HT et al. Phosphatidylinositol 3-kinase signalling is spatially organized at endosomal compartments by microtubule-associated protein 4. Nat Cell Biol 2020; 22: 1357- 1370.

[133] Thapa N , Chen M , Cryns VL et al. A p85 isoform switch enhances PI3K activation on endosomes by a MAP4- and PI3P-dependent mechanism. Cell Rep 2024; 43: 114119.

[134] Toulany M , Iida M , Lettau K et al. Targeting HER3-dependent activation of nuclear AKT improves radiotherapy of nonsmall cell lung cancer. Radiother Oncol 2022; 174: 92- 100.

[135] Tran CS , Kersten J , Yan J et al. Phosphatidylinositol 4-kinase III alpha governs cytoskeletal organization for invasiveness of liver cancer cells. Gastroenterology 2024; 167: 522- 537.

[136] Tribble EK , Ivanova PT , Grabon A et al. Quantitative profiling of the endonuclear glycerophospholipidome of murine embryonic fibroblasts. J Lipid Res 2016; 57: 1492- 1506.

[137] Turner N , Moretti E , Siclari O et al. Targeting triple negative breast cancer: Is p53 the answer? Cancer Treat Rev 2013; 39: 541- 550.

[138] Vallejo-Díaz J , Chagoyen M , Olazabal-Morán M et al. The opposing roles of PIK3R1/p85α and PIK3R2/p85β in cancer. Trends in Cancer 2019; 5: 233- 244.

[139] Vara JAF , Casado E , de Castro J et al. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 2004; 30: 193- 204.

[140] Vasko V , Saji M , Hardy E et al. Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer. J Med Genet 2004; 41: 161- 170.

[141] Visnjic D , Crljen V , Curic J et al. The activation of nuclear phosphoinositide 3-kinase C2β in all-trans-retinoic aciddifferentiated HL-60 cells. FEBS Lett 2002; 529: 268- 274.

[142] Wainstein E , Maik-Rachline G , Blenis J et al. AKTs do not translocate to the nucleus upon stimulation but AKT3 can constitutively signal from the nuclear envelope. Cell Rep 2022; 41: 111733.

[143] Walerych D , Napoli M , Collavin L et al. The rebel angel: mutant p53 as the driving oncogene in breast cancer. Carcinogenesis 2012; 33: 2007- 2017.

[144] Walerych D , Lisek K , Del Sal G . Mutant p53: one, no one, and one hundred thousand. Front Oncol 2015; 5: 289.

[145] Wang Y-H , Sheetz MP . When PIP2 meets p53: nuclear phosphoinositide signaling in the DNA damage response. Front Cell Dev Biol 2022; 10: 903994.

[146] Wang Y , Helland A , Holm R et al. TP53 mutations in earlystage ovarian carcinoma, relation to long-term survival. Br J Cancer 2004a; 90: 678- 685.

[147] Wang Y , Kringen P , Kristensen GB et al. Effect of the codon 72 polymorphism (c.215G>C, p.Arg72Pro) in combination with somatic sequence variants in the TP53 gene on survival in patients with advanced ovarian carcinoma. Hum Mutat 2004b; 24: 21- 34.

[148] Wen T , Chen M , Cryns VL et al. Regulation of the poly(A) polymerase Star-PAP by a nuclear phosphoinositide signalosome. bioRxiv 2024: 2024.07.01.601467.

[149] Wong LH , Gatta AT , Levine TP . Lipid transfer proteins: the lipid commute via shuttles, bridges and tubes. Nat Rev Mol Cell Biol 2019; 20: 85- 101.

[150] Xu R , Sen N , Paul BD et al. Inositol polyphosphate multikinase is a coactivator of p53-mediated transcription and cell death. Sci Signal 2013; 6: ra22.

[151] Xue G , Hemmings BA . PKB/Akt-dependent regulation of cell motility. J Natl Cancer Inst 2013; 105: 393- 404.

[152] Yang Y , Lee M , Fairn GD . Phospholipid subcellular localization and dynamics. J Biol Chem 2018; 293: 6230- 6240.

[153] Yeudall WA , Wrighton KH , Deb S . Mutant p53 in cell adhesion and motility. Methods Mol Biol 2013; 962: 135- 146.

[154] Yoeli-Lerner M , Yiu GK , Rabinovitz I et al. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 2005; 20: 539- 550.

[155] Yoo SH , Huh YH , Huh SK et al. Localization and projected role of phosphatidylinositol 4-kinases IIα and IIβ in inositol 1,4,5-trisphosphate-sensitive nucleoplasmic Ca²⁺ store vesicles. Nucleus 2014; 5: 341- 351.

[156] Yue X , Zhang C , Zhao Y et al. Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression. Genes Dev 2017; 31: 1641- 1654.

[157] Zhang X , Tang N , Hadden TJ et al. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 2011; 1813: 1978- 1986.

[158] Zou J , Marjanovic J , Kisseleva MV et al. Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis. Proc Natl Acad Sci USA 2007; 104: 16834- 16839.

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