title: GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy.
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-Ser(86), 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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.
authors.forename: Shu-Yong
authors.initials: SY
authors.lastname: Lin
authors.forename: Terytty Yang
authors.initials: TY
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Cixiong
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Shi-Meng
authors.initials: SM
authors.lastname: Zhang
authors.forename: Guili
authors.initials: G
authors.lastname: Lian
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Ka
authors.initials: K
authors.lastname: Ruan
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Chen-Song
authors.initials: CS
authors.lastname: Zhang
authors.forename: Kun-Yi
authors.initials: KY
authors.lastname: Chien
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wu
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Li
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
mesh_terms: D000818:Animals; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D002460:Cell Line; D045744:Cell Line, Tumor; D003470:Culture Media; D016895:Culture Media, Serum-Free; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D003470:Culture Media; D016895:Culture Media, Serum-Free; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015534:Trans-Activators; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5; D000071189:Autophagy-Related Protein-1 Homolog; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D005947:Glucose