RGS4 and RGS5 are in vivo of the N-end rule pathway

Min Jae Lee, Takafumi Tasaki, Kayoko Moroi, Jee Young An, Sadao Kimura, Ilia V. Davydov, Yongtae Kwon

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

The ATE1-encoded Arg-transferase mediates conjugation of Arg to N-terminal Asp, Glu, and Cys of certain eukaryotic proteins, yielding N-terminal Arg that can act as a degradation signal for the ubiquitin-dependent N-end rule pathway. We have previously shown that mouse ATE1-/- embryos die with defects in heart development and angiogenesis. Here, we report that the ATE1 Arg-transferase mediates the in vivo degradation of RGS4 and RGS5, which are negative regulators of specific G proteins whose functions include cardiac growth and angiogenesis. The proteolysis of these regulators of G protein signaling (RGS) proteins was perturbed either by hypoxia or in cells lacking ubiquitin ligases UBR1 and/or UBR2. Mutant RGS proteins in which the conserved Cys-2 residue could not become N-terminal were long-lived in vivo. We propose a model in which the sequential modifications of RGS4, RGS5, and RGS16 (N-terminal exposure of their Cys-2, its oxidation, and subsequent arginylation) act as a licensing mechanism in response to extracellular and intracellular signals before the targeting for proteolysis by UBR1 and UBR2. We also show that ATE1-/- embryos are impaired in the activation of extracellular signal-regulated kinase mitogen-activated protein kinases and in the expression of G protein-induced downstream effectors such as Jun, cyclin D1, and β-myosin heavy chain. These results establish RGS4 and RGS5 as in vivo substrates of the mammalian N-end rule pathway and also suggest that the O 2-ATE1-UBR1/UBR2 proteolytic circuit plays a role in RGS-regulated G protein signaling in the cardiovascular system.

Original languageEnglish
Pages (from-to)15030-15035
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number42
DOIs
StatePublished - 18 Oct 2005

Fingerprint

RGS Proteins
GTP-Binding Proteins
Transferases
Ubiquitin
Proteolysis
Embryonic Structures
GTP-Binding Protein Regulators
Myosin Heavy Chains
Cyclin D1
Extracellular Signal-Regulated MAP Kinases
Licensure
Ligases
Cardiovascular System
Mitogen-Activated Protein Kinases
Growth
Proteins

Keywords

  • ATE1 R-transferase
  • G protein signaling
  • Oxidation
  • UBR
  • Ubiquitin

Cite this

Lee, Min Jae ; Tasaki, Takafumi ; Moroi, Kayoko ; An, Jee Young ; Kimura, Sadao ; Davydov, Ilia V. ; Kwon, Yongtae. / RGS4 and RGS5 are in vivo of the N-end rule pathway. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 42. pp. 15030-15035.
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RGS4 and RGS5 are in vivo of the N-end rule pathway. / Lee, Min Jae; Tasaki, Takafumi; Moroi, Kayoko; An, Jee Young; Kimura, Sadao; Davydov, Ilia V.; Kwon, Yongtae.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 42, 18.10.2005, p. 15030-15035.

Research output: Contribution to journalArticle

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AU - Tasaki, Takafumi

AU - Moroi, Kayoko

AU - An, Jee Young

AU - Kimura, Sadao

AU - Davydov, Ilia V.

AU - Kwon, Yongtae

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