GSK3B induces autophagy by phosphorylating ULK1 |
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Authors: | Hye Young Ryu Leah Eunjung Kim Hyeonjeong Jeong Bo Kyoung Yeo Ji-Won Lee Hyeri Nam Shinwon Ha Hyun-Kyu An Hyunhee Park Seonghee Jung Kyung Min Chung Jiyea Kim Byung-Hoon Lee Heesun Cheong Eun-Kyoung Kim Seong-Woon Yu |
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Institution: | 1.Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea ;2.Division of Cancer Biology, Research Institute, National Cancer Center, 10408 Goyang, Republic of Korea ;3.Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea ;4.Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea |
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Abstract: | Unc-51-like autophagy activating kinase 1 (ULK1), a mammalian homolog of the yeast kinase Atg1, has an essential role in autophagy induction. In nutrient and growth factor signaling, ULK1 activity is regulated by various posttranslational modifications, including phosphorylation, acetylation, and ubiquitination. We previously identified glycogen synthase kinase 3 beta (GSK3B) as an upstream regulator of insulin withdrawal-induced autophagy in adult hippocampal neural stem cells. Here, we report that following insulin withdrawal, GSK3B directly interacted with and activated ULK1 via phosphorylation of S405 and S415 within the GABARAP-interacting region. Phosphorylation of these residues facilitated the interaction of ULK1 with MAP1LC3B and GABARAPL1, while phosphorylation-defective mutants of ULK1 failed to do so and could not induce autophagy flux. Furthermore, high phosphorylation levels of ULK1 at S405 and S415 were observed in human pancreatic cancer cell lines, all of which are known to exhibit high levels of autophagy. Our results reveal the importance of GSK3B-mediated phosphorylation for ULK1 regulation and autophagy induction and potentially for tumorigenesis.Subject terms: Macroautophagy, Phosphorylation |
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