MAPK15 is part of the ULK complex and controls its activity to regulate early phases of the autophagic process.

Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE

Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology

Autophagy/*physiology ; Autophagy-Related Protein-1 Homolog/*physiology ; Extracellular Signal-Regulated MAP Kinases/*physiology ; Intracellular Signaling Peptides and Proteins/*physiology ; Signal Transduction/*physiology; Autophagosomes/physiology ; Autophagy-Related Protein-1 Homolog/genetics ; Autophagy-Related Protein-1 Homolog/metabolism ; Down-Regulation ; Extracellular Signal-Regulated MAP Kinases/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Multiprotein Complexes/physiology ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/physiology ; RNA, Small Interfering/genetics

Autophagy, a pathway for bulk protein degradation and removal of damaged organelles, represents one of the major responses of cells to stress, thereby exerting a strict control on their correct functioning. Consequently, this process has been involved in the pathogenesis and therapeutic responses of several human diseases. Mitogen-activated protein (MAP) kinase 15 (MAPK15) is an atypical member of the MAP kinase family that recently emerged as a key modulator of autophagy and, through this, of cell transformation. Still, no information is available about signaling pathways mediating the effect of MAPK15 on this process, nor is it known which phase of autophagosome biogenesis is affected by this MAP kinase. Here, we demonstrate that MAPK15 stimulated 5'-AMP-activated protein kinase-dependent activity of UNC-51-like kinase 1 (ULK1), the only protein kinase among the ATG-related proteins, toward downstream substrates and signaling intermediates. Importantly, MAPK15 directly interacted with the ULK1 complex and mediated ULK1 activation induced by starvation, a classical stimulus for the autophagic process. In turn, ULK1 and its highly homologous protein ULK2 are able to transduce MAPK15 signals stimulating early phases of autophagosomal biogenesis in a multikinase cascade that offers numerous potential targets for future therapeutic intervention in cancer and other autophagy-related human diseases.
(© 2018 Colecchia et al.)

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Keywords: autophagy; cell signaling; mitogen-activated protein kinase (MAPK); trafficking; vesicles

0 (Intracellular Signaling Peptides and Proteins)
0 (Multiprotein Complexes)
0 (RNA, Small Interfering)
EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.11.1 (ULK1 protein, human)
EC 2.7.11.1 (Ulk2 protein, human)
EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
EC 2.7.11.24 (MAPK15 protein, human)

Date Created: 20180823 Date Completed: 20190422 Latest Revision: 20211204

20240829

PMC6187625

10.1074/jbc.RA118.002527

30131341