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• W2462649340 endingPage "390" @default.
• W2462649340 startingPage "378" @default.
• W2462649340 abstract "Although the oncogenic PI3K/Akt/mTORC1 cascade is well established in cancer, PI(4,5)P2 and PIPKI/PIPKII functions are also integral parts of cancer progression. The phosphoinositide signaling axis in cancer is collectively regulated by PI(4,5)P2 and PI(3,4,5)P3 lipid messengers and their generating enzymes PIPK and PI3K, both of which are overexpressed in cancer. PI(4,5)P2 and PIPKI/PIPKII not only regulate cell polarity, motility, and invasion but also control PI3K/Akt activation in cancer. Co-targeting of the PI(4,5)P2 signaling nexus may enhance the efficacy of canonical anticancer drugs targeting PI3K/Akt. Phosphoinositide 3-kinase (PI3K) generation of PI(3,4,5)P3 from PI(4,5)P2 and the subsequent activation of Akt and its downstream signaling cascades (e.g., mTORC1) dominate the landscape of the phosphoinositide signaling axis in cancer research. However, PI(4,5)P2 is breaking its boundary as merely a substrate for PI3K and phospholipase C (PLC) and is now an established lipid messenger pivotal for various cellular events in cancer. Here we review the phosphoinositide signaling axis in cancer, giving due weight to PI(4,5)P2 and its generating enzymes, the phosphatidylinositol (PI) phosphate (PIP) kinases (PIPKs). We highlight how PI(4,5)P2 and PIPKs serve as a proximal node in the phosphoinositide signaling axis and how interaction with cytoskeletal proteins regulates the migratory and invasive nexus of metastasizing tumor cells. Phosphoinositide 3-kinase (PI3K) generation of PI(3,4,5)P3 from PI(4,5)P2 and the subsequent activation of Akt and its downstream signaling cascades (e.g., mTORC1) dominate the landscape of the phosphoinositide signaling axis in cancer research. However, PI(4,5)P2 is breaking its boundary as merely a substrate for PI3K and phospholipase C (PLC) and is now an established lipid messenger pivotal for various cellular events in cancer. Here we review the phosphoinositide signaling axis in cancer, giving due weight to PI(4,5)P2 and its generating enzymes, the phosphatidylinositol (PI) phosphate (PIP) kinases (PIPKs). We highlight how PI(4,5)P2 and PIPKs serve as a proximal node in the phosphoinositide signaling axis and how interaction with cytoskeletal proteins regulates the migratory and invasive nexus of metastasizing tumor cells. PI is a lipid signaling molecule in the inner leaflet of the plasma membrane. It comprises two fatty acid chains linked to a glycerol moiety and a water-soluble inositol head group. The hydroxyl groups (at the 3, 4, and 5 positions) in the inositol ring can be phosphorylated in various combinations resulting in seven distinct and interconvertible phosphoinositides: PI3P, PI4P, PI5P, PI(3,4)P2, PI(3,5)P2, PI(4,5)P2, and PI(3,4,5)P3. This is achieved by various PI or phosphoinositide kinases and phosphatases that are expressed in the cell. These molecules account for less than 1–5% of the total phospholipid content of mammalian cells. PI phosphorylated at the fourth position (PI4P) of the inositol ring is the most abundant of these phosphoinositides in the cell. It is followed by PI 4,5-bisphosphate [PI(4,5)P2], which is phosphorylated at the fourth and fifth positions. lipid kinases that phosphorylate phosphoinositides (e.g., PI3P, PI4P, PI5P) in cells and are classified as type I, II, and III. Type I and type II PIPKs generate PI(4,5)P2 in cells. lipid kinases that phosphorylate the 3-OH group of the inositol ring in PI to form PI3P, PI(3,4)P2, and PI(3,4,5)P3. Depending on their structure and substrate specificity, these are categorized as class I, II, and III. Class I is the dominant member in cell signaling and cancer biology and is activated downstream of RTKs, GPCRs, and adhesion receptors. Class IA PI3Ks are heterodimeric molecules comprising regulatory (five variants: p85α, p85β, p85γ, p55α, and p50α) and catalytic (three variants: p110α, p110β, and p110δ) subunits. Class IB PI3K comprises a p110γ catalytic subunit. PI3K enzymes with catalytic subunits p110α and p110β are the most ubiquitously expressed. Class II PI3K produces PI3P and PI(3,4)P2 whereas class III PI3K produces only PI3P." @default.
• W2462649340 created "2016-07-22" @default.
• W2462649340 creator A5015582793 @default.
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• W2462649340 date "2016-07-01" @default.
• W2462649340 modified "2023-10-18" @default.
• W2462649340 title "The Hidden Conundrum of Phosphoinositide Signaling in Cancer" @default.
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