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Article: DAPK3 inhibits gastric cancer progression via activation of ULK1-dependent autophagy

TitleDAPK3 inhibits gastric cancer progression via activation of ULK1-dependent autophagy
Authors
Issue Date2021
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cdd
Citation
Cell Death and Differentiation, 2021, v. 28, p. 952-967 How to Cite?
AbstractDysregulation of the balance between cell proliferation and cell death is a central feature of malignances. Death-associated protein kinase 3 (DAPK3) regulates programmed cell death including apoptosis and autophagy. Our previous study showed that DAPK3 downregulation was detected in more than half of gastric cancers (GCs), which was related to tumor invasion, metastasis, and poor prognosis. However, the precise molecular mechanism underlying DAPK3-mediated tumor suppression remains unclear. Here, we showed that the tumor suppressive function of DAPK3 was dependent on autophagy process. Mass spectrometry, in vitro kinase assay, and immunoprecipitation revealed that DAPK3 increased ULK1 activity by direct ULK1 phosphorylation at Ser556. ULK1 phosphorylation by DAPK3 facilitates the ULK1 complex formation, the VPS34 complex activation, and autophagy induction upon starvation. The kinase activity of DAPK3 and ULK1 Ser556 phosphorylation were required for DAPK3-modulated tumor suppression. The coordinate expression of DAPK3 with ULK1 Ser556 phosphorylation was confirmed in clinical GC samples, and this co-expression was correlated with favorable survival outcomes in patients. Collectively, these findings indicate that the tumor-suppressor roles of DAPK3 in GC are associated with autophagy and that DAPK3 is a novel autophagy regulator, which can directly phosphorylate ULK1 and activate ULK1. Thus, DAPK3 might be a promising prognostic autophagy-associated marker.
Persistent Identifierhttp://hdl.handle.net/10722/300920
ISSN
2020 Impact Factor: 15.828
2015 SCImago Journal Rankings: 4.219
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorLi, GM-
dc.contributor.authorLi, L-
dc.contributor.authorLi, MQ-
dc.contributor.authorChen, X-
dc.contributor.authorSu, Q-
dc.contributor.authorDeng, ZJ-
dc.contributor.authorLiu, HB-
dc.contributor.authorLi, B-
dc.contributor.authorZhang, WH-
dc.contributor.authorJia, YX-
dc.contributor.authorWang, WJ-
dc.contributor.authorMa, JY-
dc.contributor.authorZhang, HL-
dc.contributor.authorXie, D-
dc.contributor.authorZhu, XF-
dc.contributor.authorHe, YL-
dc.contributor.authorGuan, XY-
dc.contributor.authorBi, J-
dc.date.accessioned2021-07-06T03:12:03Z-
dc.date.available2021-07-06T03:12:03Z-
dc.date.issued2021-
dc.identifier.citationCell Death and Differentiation, 2021, v. 28, p. 952-967-
dc.identifier.issn1350-9047-
dc.identifier.urihttp://hdl.handle.net/10722/300920-
dc.description.abstractDysregulation of the balance between cell proliferation and cell death is a central feature of malignances. Death-associated protein kinase 3 (DAPK3) regulates programmed cell death including apoptosis and autophagy. Our previous study showed that DAPK3 downregulation was detected in more than half of gastric cancers (GCs), which was related to tumor invasion, metastasis, and poor prognosis. However, the precise molecular mechanism underlying DAPK3-mediated tumor suppression remains unclear. Here, we showed that the tumor suppressive function of DAPK3 was dependent on autophagy process. Mass spectrometry, in vitro kinase assay, and immunoprecipitation revealed that DAPK3 increased ULK1 activity by direct ULK1 phosphorylation at Ser556. ULK1 phosphorylation by DAPK3 facilitates the ULK1 complex formation, the VPS34 complex activation, and autophagy induction upon starvation. The kinase activity of DAPK3 and ULK1 Ser556 phosphorylation were required for DAPK3-modulated tumor suppression. The coordinate expression of DAPK3 with ULK1 Ser556 phosphorylation was confirmed in clinical GC samples, and this co-expression was correlated with favorable survival outcomes in patients. Collectively, these findings indicate that the tumor-suppressor roles of DAPK3 in GC are associated with autophagy and that DAPK3 is a novel autophagy regulator, which can directly phosphorylate ULK1 and activate ULK1. Thus, DAPK3 might be a promising prognostic autophagy-associated marker.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cdd-
dc.relation.ispartofCell Death and Differentiation-
dc.titleDAPK3 inhibits gastric cancer progression via activation of ULK1-dependent autophagy-
dc.typeArticle-
dc.identifier.emailLi, L: lilei728@HKUCC-COM.hku.hk-
dc.identifier.emailGuan, XY: xyguan@hku.hk-
dc.identifier.authorityGuan, XY=rp00454-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/s41418-020-00627-5-
dc.identifier.pmid33037394-
dc.identifier.pmcidPMC7937684-
dc.identifier.scopuseid_2-s2.0-85092412329-
dc.identifier.hkuros323253-
dc.identifier.volume28-
dc.identifier.spage952-
dc.identifier.epage967-
dc.publisher.placeUnited Kingdom-

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