Journal Article

GSK3-TIP60-ULK1 Signaling Pathway Links Growth Factor Deprivation to Autophagy

Li, Xiaotong, Chien, Kun-Yi, Zhang, Cixiong, Wang, Zhen, Lin, Shu-Yong, Chen, Yan, Li, Terytty Yang, Liu, Qi, Zhang, Chen-Song, Zhang, Shi-Meng, Li, Qinxi, Ruan, Ka, Wu, Jiawei, Liu, Qing, Han, Jiahuai, Lian, Guili, Lin, Sheng-Cai

2012

Overview

In metazoans, cells depend on extracellular growth factors for energy homeostasis. We found that glycogen synthase kinase-3 (GSK3), when deinhibited by default in cells deprived of growth factors, activates acetyltransferase TIP60 through phosphorylating TIP60-Ser⁸⁶, which directly acetylates and stimulates the protein kinase ULK1, which is required for autophagy. Cells engineered to express TIP60 S86A that cannot be phosphorylated by GSK3 could not undergo serum deprivation-induced autophagy. An acetylation-defective mutant of ULK1 failed to rescue autophagy in ULK1 -/- mouse embryonic fibroblasts. Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy when deprived of serum but not glucose. These findings uncover an activating pathway that integrates protein phosphorylation and acetylation to connect growth factor deprivation to autophagy.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Acetylation / Animalia / Animals / Antibodies / Autophagy / Autophagy-Related Protein-1 Homolog / Biological and medical sciences / blood serum / Cell growth / Cell Line / Cell Line, Tumor / Cell lines / Cell physiology / Cells / Cellular biology / Culture Media / Culture Media, Serum-Free / energy / fibroblasts / Fundamental and applied biological sciences. Psychology / glucose / Glucose - metabolism / glycogen (starch) synthase / Glycogen Synthase Kinase 3 - genetics / Glycogen Synthase Kinase 3 - metabolism / Glycogen Synthase Kinase 3 beta / Growth factors / HCT116 cells / HEK293 Cells / Histone Acetyltransferases - genetics / Histone Acetyltransferases - metabolism / Histones / Homeostasis / Humans / Inductive reasoning / Intercellular Signaling Peptides and Proteins - metabolism / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / Lysine Acetyltransferase 5 / Mammals / Mice / Microbiology / Molecular and cellular biology / mutants / Pathways / Phosphorylation / protein kinases / protein phosphorylation / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Proteins / Rats / Serums / Signal Transduction / T lymphocytes / Trans-Activators - genetics / Trans-Activators - metabolism / Yeast / Yeasts