The tumor suppressor PTEN is a dual protein and phosphoinositide phosphatase that negatively controls the phosphatidylinositol (PI) 3-kinase/protein kinase B (Akt/PKB) signaling pathway. Interleukin-13 via the activation of the class I PI 3-kinase has been shown to inhibit the macroautophagic pathway in the human colon cancer HT-29 cells. Here we demonstrate that the wild-type PTEN is expressed in this cell line. Its overexpression directed by an inducible promoter counteracts the interleukin-13 down-regulation of macroautophagy. This effect was dependent upon the phosphoinositide phosphatase activity of PTEN as determined by using the mutant G129E, which has only protein phosphatase activity. The role of Akt/PKB in the signaling control of interleukin-13-dependent macroautophagy was investigated by expressing a constitutively active form of the kinase ( Myr PKB). Under these conditions a dramatic inhibition of macroautophagy was observed. By contrast a high rate of autophagy was observed in cells expressing a dominant negative form of PKB. These data demonstrate that the signaling control of macroautophagy overlaps with the well known PI 3-kinase/PKB survival pathway and that the loss of PTEN function in cancer cells inhibits a major catabolic pathway.

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ABSTRACT. Macroautophagy is a major lysosomal catabolic process conserved from yeast to human. The formation of autophagic vacuoles is stimulated by a variety of intracellular and extracellular stress situations including amino acid starvation, aggregation of misfolded proteins, and accumulation of damaged organelles. Several signaling pathways control the formation of autophagic vacuoles. As some of them are engaged in the control of protein synthesis or cell survival this suggests that macroautophagy is intimately associated with the execution of cell proliferation and cell death programms. Whether or not these different signaling pathways converge to a unique point to trigger the formation of autophagic vacuole remains an open question.Key words: autophagy/lysosomes/proteolysis/signal transduction Macroautophagy or autophagy is a ubiquitous catabolic pathway terminating in the lysosomal compartment, which contributes to cellular homeostasis by regulating the equilibrium between amino acids and proteins. Recently, studies have shed light on different molecular control elements, which are common to eukaryotic cells, from yeast to human, suggesting a well-conserved degradative pathway. Autophagy is induced as a response to both extracellular stress conditions (nutrient deprivation, hypoxia) and intracellular stress conditions (accumulation of damaged organelles, aggregation of proteins). The large number of stimuli able to trigger macroautophagy suggests the implication of multiple signaling pathways responsible for the formation of autophagosomes. The aim of this review is to give insight into the different signaling pathways engaged in the control of macroautophagy in mammalian cells.