Autophagic Punctum

Protein phosphorylation-acetylation cascade connects growth factor deprivation to autophagy

Volume 8, Issue 9   September 2012
Pages 1385 - 1386
http://dx.doi.org/10.4161/auto.20959
Keywords: GSK3, Tip60, Ulk1, acetylation, autophagy, growth factor, phosphorylation
Authors: Shu-Yong Lin, Terytty Yang Li, Qing Liu, Cixiong Zhang, Xiaotong Li, Yan Chen, Shi-Meng Zhang, Guili Lian, Qi Liu, Ka Ruan, Zhen-Bo Wang, Chen-Song Zhang, Kun-Yi Chien, Jiawei Wu, Qinxi Li, Jiahuai Han and Sheng-Cai Lin

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Abstract:
Different from unicellular organisms, metazoan cells require the presence of extracellular growth factors to utilize environmental nutrients. However, the underlying mechanism was unclear. We have delineated a pathway, in which glycogen synthase kinase 3 (GSK3) in cells deprived of growth factors phosphorylates and activates the acetyltransferase KAT5/TIP60, which in turn stimulates the protein kinase ULK1 to elicit autophagy. Cells with the Kat5/Tip60 gene replaced with Kat5S86A that cannot be phosphorylated by GSK3 are resistant to serum starvation-induced autophagy. Acetylation sites on ULK1 were mapped to K162 and K606, and the acetylation-defective mutant ULK1K162,606R displays reduced kinase activity and fails to rescue autophagy in Ulk1−/− mouse embryonic fibroblasts, indicating that acetylation is vital to the activation of ULK1. The GSK3-KAT5-ULK1 cascade seems to be specific for cells to sense growth factors, as KAT5 phosphorylation is not enhanced under glucose deprivation. Distinct from the glucose starvation-autophagy pathway that is conserved in all eukaryotic organisms, the growth factor deprivation response pathway is perhaps unique to metazoan organisms.

Autophagic Punctum to:
SY Lin, TY Li, Q Liu, C Zhang, X Li, Y Chen, et al. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 2012; 336: 477-81
PMID: 22539723 DOI: 10.1126/science.1217032

Received: May 23, 2012; Accepted: May 31, 2012; Published Online: June 21, 2012

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