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The pathway initiates with the recruitment of phosphatidylinositol\u20103 kinases (PI3Ks) onto the plasma membrane, generating phosphatidylinositol\u20103,4,5\u2010triphosphate [PtdIns(3,4,5)P<jats:sub>3<\/jats:sub>] and subsequently activating AKT. Being the central node of the PI3K network, AKT activates the mechanistic target of rapamycin kinase complex 1 (MTORC1) via Tuberous sclerosis complex 2 inhibition in the cytoplasm. Although the cytoplasmic role of the pathway has been widely explored for decades, we now know that most of the effector molecules of the PI3K axis diverge from the canonical route and translocate to other cell organelles including the nucleus. The presence of phosphoinositides (PtdIns) inside the nucleus itself indicates the existence of a nuclear PI3K signalling. The nuclear localization of these signaling components is evident in regulating many nuclear processes like DNA replication, transcription, DNA repair, maintenance of genomic integrity, chromatin architecture, and cell cycle control. Here, our review intends to present a comprehensive overview of the nuclear functions of the PI3K\u2010AKT\u2010MTOR signaling biomolecules.<\/jats:p>","DOI":"10.1002\/jcp.30782","type":"journal-article","created":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T12:31:26Z","timestamp":1653568286000},"page":"3181-3204","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The non\u2010canonical nuclear functions of key players of the PI3K\u2010AKT\u2010MTOR pathway"],"prefix":"10.1002","volume":"237","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5820-2391","authenticated-orcid":false,"given":"Sakshi","family":"Gupta","sequence":"first","affiliation":[{"name":"Department of Molecular Reproduction, Development &amp; Genetics Indian Institute of Science  Bangalore Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7680-4166","authenticated-orcid":false,"given":"Mukund","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development &amp; Genetics Indian Institute of Science  Bangalore Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6260-4959","authenticated-orcid":false,"given":"Soumi","family":"Chaudhuri","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development &amp; Genetics Indian Institute of Science  Bangalore Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0537-6560","authenticated-orcid":false,"given":"Arun","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development &amp; Genetics Indian Institute of Science  Bangalore Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,26]]},"reference":[{"issue":"7","key":"e_1_2_14_2_1","first-page":"1957","article-title":"The proteins encoded by c\u2010akt and v\u2010akt differ in post\u2010translational modification, subcellular localization and oncogenic potential","volume":"8","author":"Ahmed N. 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