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

Ryo Yoshizawa, Nobuhisa Umeki, Akihiro Yamamoto, Mariko Okada, Masayuki Murata, Yasushi Sako

Molecular biology of the cell 2021 Sep 01

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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.

Citation

Ryo Yoshizawa, Nobuhisa Umeki, Akihiro Yamamoto, Mariko Okada, Masayuki Murata, Yasushi Sako. p52Shc regulates the sustainability of ERK activation in a RAF-independent manner. Molecular biology of the cell. 2021 Sep 01;32(19):1838-1848