ATG1, an autophagy regulator, inhibits cell growth by negatively regulating S6 kinase

Lee, S. B. et al., EMBO reports 8, 360–365 (2007)

Abstract

To endure starvation and other stresses, cells undergo a lysosomal process of cytoplasmic degradation known as autophagy.  Autophagy has been implicated in a number of cellular and developmental processes, such as cell growth control.  Autophagy is promoted by several tumor suppressor genes including PTEN, TSC1 and 2, and inhibited by growth-promoting pathways such as class I PI3K and target of rapamycin (TOR) signaling under growth factor stimulation (1).  However, direct evidence of a role for autophagy in regulating cell growth is lacking.  To investigate the relationship between autophagy and cell growth regulation, the authors examined the interactions between the representative components of the two pathways, autophagy-specific gene 1 (ATG1) and TOR/p70 S6 kinase (S6K).  ATG1 is a Ser/Thr protein kinase and induces autophagosome formation which is negatively regulated by TOR signaling (2).  TOR/S6K signaling can initiate translation and lead to cell growth.  They found that the double mutants of Drosophila TOR (dTOR) and ATG1 (DmATG1) grew faster than the dTOR mutant, and partially rescued the reduced cell and nuclear size phenotype of the dTOR mutant.  These results implicated that DmATG1 may negatively regulate dTOR pathway in Drosophila.  The phosphorylation levels of Drosophila S6K (dS6K) were increased in the DmATG1 mutants.  Transfection of siRNA targeting ATG1 enhanced the increased phosphorylation of S6K in mammalian cells.  Overexpression of ATG1 strongly inhibited S6K activity induced by nutrient supplement.  Moreover, they determined that ATG1 specifically suppressed S6K activity by blocking phosphorylation of S6K at Thr 389.  Together, these results demonstrate the presence of crosstalk between ATG1 and S6K signaling, in which ATG1 inhibits S6K and, consequently, suppresses cell growth.

References

1.      Scott, R. C., Schuldiner, O. and Neufeld, T. P. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7, 167–178 (2004).

2.      Kamada, Y., Funakoshi. T., Shintani, T., Nagano, K., Ohsumi, M., and Ohsumi, Y. TOR-mediated induction of autophagy via an Apg1 protein kinase complex. J. Cell Biol. 150, 1507–1513 (2000).