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Science 336 (6080): 477-481

Copyright © 2012 by the American Association for the Advancement of Science

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

Shu-Yong Lin,1,* Terytty Yang Li,1,* Qing Liu,1 Cixiong Zhang,1 Xiaotong Li,1 Yan Chen,1 Shi-Meng Zhang,2 Guili Lian,1 Qi Liu,1 Ka Ruan,1 Zhen Wang,1 Chen-Song Zhang,1 Kun-Yi Chien,3 Jiawei Wu,4 Qinxi Li,1 Jiahuai Han,1 Sheng-Cai Lin1,{dagger}

Abstract: 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 TIP60S86A 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.

1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian 361005, China.
2 Beijing Institute of Radiation Medicine, Beijing 100850, China.
3 Molecular Medicine Research Center, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan.
4 School of Life Science, Tsinghua University, Beijing 100101, China.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: linsc{at}xmu.edu.cn


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