PI3K-Akt-mTOR Signaling in Cancer and Cancer Therapeutics

Chopra, Sameer; Cantley, Lewis C.

doi:10.1007/978-3-319-34211-5_1

Cited by 1 publication

(2 citation statements)

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“…Proteins with pleckstrin homology (PH) domains such AKT and PDK1 bind to membrane bound PtdIns(3,4,5)P 3 on the inner wall of the plasma membrane and on early endosomes [11,13]. Once bound to PtdIns(3,4,5)P 3 , AKT is phosphorylated by PDK1 at Thr308 and the mTORC2 complex at Ser473 and becomes fully active [11,14]. Activated AKT phosphorylates numerous cytosolic and nuclear targets including GSK3β, PRAS40, FOXO, mTORC1 and p27 to regulate cell metabolism, proliferation, survival, and migration [14].…”

Section: The Phosphoinositide-3-kinase (Pi3k) Signalling Pathwaymentioning

confidence: 99%

“…Once bound to PtdIns(3,4,5)P 3 , AKT is phosphorylated by PDK1 at Thr308 and the mTORC2 complex at Ser473 and becomes fully active [11,14]. Activated AKT phosphorylates numerous cytosolic and nuclear targets including GSK3β, PRAS40, FOXO, mTORC1 and p27 to regulate cell metabolism, proliferation, survival, and migration [14].…”

Section: The Phosphoinositide-3-kinase (Pi3k) Signalling Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer

Csolle

Ooms

Papa

et al. 2020

IJMS

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The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P3 at the plasma membrane in response to growth factor stimulation, leading to AKT activation to drive cell proliferation, survival and migration. PTEN negatively regulates PI3K/AKT signalling by dephosphorylating PtdIns(3,4,5)P3 to form PtdIns(4,5)P2. PtdIns(3,4,5)P3 can also be hydrolysed by the inositol polyphosphate 5-phosphatases (5-phosphatases) to produce PtdIns(3,4)P2. Interestingly, while PTEN is a bona fide tumour suppressor and is frequently mutated/lost in breast cancer, 5-phosphatases such as PIPP, SHIP2 and SYNJ2, have demonstrated more diverse roles in regulating mammary tumourigenesis. Reduced PIPP expression is associated with triple negative breast cancers and reduced relapse-free and overall survival. Although PIPP depletion enhances AKT phosphorylation and supports tumour growth, this also inhibits cell migration and metastasis in vivo, in a breast cancer oncogene-driven murine model. Paradoxically, SHIP2 and SYNJ2 are increased in primary breast tumours, which correlates with invasive disease and reduced survival. SHIP2 or SYNJ2 overexpression promotes breast tumourigenesis via AKT-dependent and independent mechanisms. This review will discuss how PTEN, PIPP, SHIP2 and SYNJ2 distinctly regulate multiple functional targets, and the mechanisms by which dysregulation of these distinct phosphoinositide phosphatases differentially affect breast cancer progression.

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