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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Published on: July 17, 2019

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

Ryo Yoshizawa1,2, Nobuhisa Umeki1, Akihiro Yamamoto1

  • 1Cellular Informatics Lab, RIKEN, Wako, Saitama 351-0198, Japan.

Molecular Biology of the Cell
|July 14, 2021
PubMed

Insights

p52SHC (SHC) adaptor proteins sustain ERK pathway activation, unlike GRB2. SHC

Area of Science:

  • Cellular signaling and signal transduction pathways.
  • Molecular mechanisms of receptor tyrosine kinase signaling.
  • Adaptor protein function in cell communication.

Background:

  • p52SHC (SHC) and GRB2 are key adaptor proteins in the RAS/MAPK (ERK) pathway.
  • This pathway transmits signals from cell-surface receptors to regulate cellular functions.
  • Understanding SHC and GRB2 roles is crucial for deciphering signal transduction.

Purpose of the Study:

  • To investigate the distinct roles of SHC and GRB2 in ERBB receptor-mediated signal transduction.
  • To analyze the translocation dynamics of SHC and GRB2 upon heregulin (HRG) stimulation.
  • To determine the impact of SHC on ERK activation and subsequent nuclear translocation.

Main Methods:

  • Utilizing fluorescently labeled SHC and GRB2 to track their translocation to the cell surface.
  • Monitoring activated ERK translocation to the nucleus following ERBB receptor activation by HRG.
  • Employing SHC knockdown to assess its necessity for sustained ERK signaling.
  • Investigating the involvement of PI3K, MEK, and RAF in SHC-mediated ERK regulation.

Main Results:

  • SHC translocation dynamics were unexpectedly sustained, contrasting with transient GRB2 translocation.
  • Sustained SHC localization correlated positively with sustained nuclear ERK localization.
  • SHC knockdown led to more transient ERK nuclear translocation.
  • SHC-mediated PI3K activation was essential for sustained ERK translocation, impacting MEK but not RAF.
  • Overexpression of ERBB1 resulted in transient SHC translocation and a shift from differentiation to proliferation.

Conclusions:

  • SHC and GRB2 exhibit non-redundant functions in signal transduction.
  • SHC plays a critical role in the temporal regulation of ERK activation.
  • The dynamics of SHC and ERK translocation influence cell fate decisions, such as proliferation versus differentiation.

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