p52Shc regulates the sustainability of ERK activation in a RAF-independent manner

Mol Biol Cell. 2021 Sep 1;32(19):1838-1848. doi: 10.1091/mbc.E21-01-0007. Epub 2021 Jul 14.


p52SHC (SHC) and GRB2 are adaptor proteins involved in the RAS/MAPK (ERK) pathway mediating signals from cell-surface receptors to various cytoplasmic proteins. To further examine their roles in signal transduction, we studied the translocation of fluorescently labeled SHC and GRB2 to the cell surface, caused by the activation of ERBB receptors by heregulin (HRG). We simultaneously evaluated activated ERK translocation to the nucleus. Unexpectedly, the translocation dynamics of SHC were sustained when those of GRB2 were transient. The sustained localization of SHC positively correlated with the sustained nuclear localization of ERK, which became more transient after SHC knockdown. SHC-mediated PI3K activation was required to maintain the sustainability of the ERK translocation regulating MEK but not RAF. In cells overexpressing ERBB1, SHC translocation became transient, and the HRG-induced cell fate shifted from a differentiation to a proliferation bias. Our results indicate that SHC and GRB2 functions are not redundant but that SHC plays the critical role in the temporal regulation of ERK activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Cell Proliferation
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • GRB2 Adaptor Protein / genetics
  • GRB2 Adaptor Protein / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • MAP Kinase Signaling System*
  • MCF-7 Cells
  • Microscopy, Fluorescence / methods
  • Src Homology 2 Domain-Containing, Transforming Protein 1 / genetics
  • Src Homology 2 Domain-Containing, Transforming Protein 1 / metabolism*
  • raf Kinases / genetics
  • raf Kinases / metabolism*


  • GRB2 Adaptor Protein
  • SHC1 protein, human
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Green Fluorescent Proteins
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases