Research ArticleCell Biology

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

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

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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.

Abstract

ErbB3 and ErbB4 are receptor tyrosine kinases that are activated by the neuregulin (NRG) family of growth factors. These receptors govern various developmental processes, and their dysregulation contributes to several human disease states. The abundance of ErbB3 and ErbB4, and thus signaling through these receptors, is limited by the E3 ubiquitin ligase Nrdp1, which targets ErbB3 and ErbB4 for degradation. Reticulons are proteins that influence the morphology of the endoplasmic reticulum (ER) by promoting the formation of tubules, a response of cells to some stressors. We found that the ER structural protein reticulon 4A (Rtn4A, also known as Nogo-A) increased ErbB3 abundance and proliferative signaling by suppressing Nrdp1 function. Rtn4A interacted with Nrdp1 and stabilized ErbB3 in an Nrdp1-dependent manner. Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules. Rtn4A knockdown in human breast tumor cells decreased ErbB3 abundance, NRG-stimulated signaling, and cellular proliferation and migration. Because proteins destined for the plasma membrane are primarily synthesized in the sheet portions of the ER, our observations suggest that Rtn4A counteracts the Nrdp1-mediated degradation of ErbB3 by sequestering the ubiquitin ligase into ER tubules. The involvement of a reticulon suggests a molecular link between ER structure and the sensitivity of cells to receptor tyrosine kinase–mediated survival signals at the cell surface.

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