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Phosphoinositide 3‐kinases as accelerators and brakes of autophagy
Author(s) -
O′Farrell Fergal,
Rusten Tor E.,
Stenmark Harald
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12486
Subject(s) - autophagy , microbiology and biotechnology , phosphatidylinositol , pi3k/akt/mtor pathway , effector , atg16l1 , kinase , phosphorylation , chemistry , intracellular , signal transduction , biology , biochemistry , apoptosis
Degradation of cytoplasmic material by autophagy plays a key role in protein homeostasis and metabolic control, as well as in the removal of intracellular protein aggregates, pathogens and damaged organelles. The concept of up‐ or down‐regulating this pathway pharmacologically in neurodegenerative diseases, infections, inflammation and cancer is therefore attractive. Among the key pharmacological targets in regulation of autophagy are the phosphoinositide 3‐kinases ( PI 3 K s), which mediate the phosphorylation of phosphatidylinositol (PtdIns) or PtdIns 4,5‐ bis phosphate in the 3‐position of the (phospho)inositol headgroup. The catalytic products, PtdIns 3‐phosphate (PtdIns3P) and PtdIns 3,4,5‐ tris phosphate [PtdIns(3,4,5)P 3 ], respectively, have opposing roles in autophagy. PtdIns3P, the product of class II and III PI3Ks, mediates the recruitment of specific autophagic effectors to the sites of origin of autophagic membranes and thereby plays an essential role in canonical autophagy. By contrast, PtdIns(3,4,5)P 3 , the product of class I PI3Ks, triggers the target of rapamycin signalling pathway, which inhibits autophagy. In this review, we discuss the functions of class I, II and III PI3Ks in autophagy and describe the protein effectors of PtdIns3P and PtdIns(3,4,5)P3 that promote or inhibit autophagy, respectively. We also provide examples of how PI3K‐mediated control of autophagy is relevant to an understanding of tumour suppression and progression.