Research ArticleCell Biology

The ER structural protein Rtn4A stabilizes and enhances signaling through the receptor tyrosine kinase ErbB3

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Science Signaling  28 Jun 2016:
Vol. 9, Issue 434, pp. ra65
DOI: 10.1126/scisignal.aaf1604

Linking ER remodeling to cell proliferation

The receptor tyrosine kinase ErbB3 is a cell surface transmembrane protein that is activated by the neuregulin (NRG) family of growth factors. ErbB3 promotes cell proliferation and differentiation and may help cells adapt to various stresses. The E3 ubiquitin ligase Nrdp1 limits the cell surface abundance of ErbB3 and therefore suppresses the responsiveness of cells to NRGs, by targeting newly synthesized ErbB3 for degradation at the endoplasmic reticulum (ER). Hatakeyama et al. found that the ER structural protein reticulon 4A (Rtn4A) reduced Nrdp1-dependent degradation of ErbB3 by sequestering Nrdp1 into ER tubules away from ER sheets, which are the site of synthesis of proteins destined for the plasma membrane. In cultured breast cancer cells, knocking down Rtn4A reduced ErbB3 abundance and inhibited cellular proliferation and migration in response to NRG1β. Because ER structural proteins such as Rtn4A mediate ER remodeling in response to stress, these results suggest that ER remodeling may also promote cell survival by enhancing the ability of cells to detect survival signals at the surface.

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