title: Spatial control of Shoc2-scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5.
abstract: The scaffold protein Shoc2 accelerates activity of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) pathway. Mutations in Shoc2 result in Noonan-like RASopathy, a developmental disorder with a wide spectrum of symptoms. The amplitude of the ERK1/2 signals transduced through the complex is fine-tuned by the HUWE1-mediated ubiquitylation of Shoc2 and its signaling partner RAF-1. Here, we provide a mechanistic basis of how ubiquitylation of Shoc2 and RAF-1 is controlled. We demonstrate that the newly identified binding partner of Shoc2, the (AAA+) ATPase PSMC5, triggers translocation of Shoc2 to endosomes. At the endosomes, PSMC5 displaces the E3 ligase HUWE1 from the scaffolding complex to attenuate ubiquitylation of Shoc2 and RAF-1. We show that a RASopathy mutation that changes the subcellular distribution of Shoc2 leads to alterations in Shoc2 ubiquitylation due to the loss of accessibility to PSMC5. In summary, our results demonstrate that PSMC5 is a new and important player involved in regulating ERK1/2 signal transmission through the remodeling of Shoc2 scaffold complex in a spatially-defined manner.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Eun Ryoung
authors.initials: ER
authors.lastname: Jang
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: HyeIn
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Shi
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Popa
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Myoungkun
authors.initials: M
authors.lastname: Jeoung
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA emilia.galperin@uky.edu.
authors.forename: Emilia
authors.initials: E
authors.lastname: Galperin
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C092282:PSMC5 protein, human; C112913:SHOC2 protein, human; D014157:Transcription Factors; D019908:Proto-Oncogene Proteins c-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities
keywords: ERK1/2; PSMC5; Remodeling; Scaffold; Shoc2 scaffold