praja2 regulates KSR1 stability and mitogenic signaling

Cell Death Dis. 2016 May 19;7(5):e2230. doi: 10.1038/cddis.2016.109.

Abstract

The kinase suppressor of Ras 1 (KSR1) has a fundamental role in mitogenic signaling by scaffolding components of the Ras/MAP kinase pathway. In response to Ras activation, KSR1 assembles a tripartite kinase complex that optimally transfers signals generated at the cell membrane to activate ERK. We describe a novel mechanism of ERK attenuation based on ubiquitin-dependent proteolysis of KSR1. Stimulation of membrane receptors by hormones or growth factors induced KSR1 polyubiquitination, which paralleled a decline of ERK1/2 signaling. We identified praja2 as the E3 ligase that ubiquitylates KSR1. We showed that praja2-dependent regulation of KSR1 is involved in the growth of cancer cells and in the maintenance of undifferentiated pluripotent state in mouse embryonic stem cells. The dynamic interplay between the ubiquitin system and the kinase scaffold of the Ras pathway shapes the activation profile of the mitogenic cascade. By controlling KSR1 levels, praja2 directly affects compartmentalized ERK activities, impacting on physiological events required for cell proliferation and maintenance of embryonic stem cell pluripotency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Colforsin / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Fibroblast Growth Factor 2 / pharmacology
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase 1 / genetics*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogens / pharmacology
  • Models, Molecular
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / drug effects
  • Mouse Embryonic Stem Cells / metabolism
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Protein Kinases / chemistry
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism
  • Protein Stability
  • Proteolysis
  • Sequence Alignment
  • Signal Transduction*
  • Structural Homology, Protein
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • Mitogens
  • Fibroblast Growth Factor 2
  • Colforsin
  • Epidermal Growth Factor
  • PJA2 protein, human
  • Ubiquitin-Protein Ligases
  • Protein Kinases
  • KSR-1 protein kinase
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3