Most eukaryotic transmembrane and secreted proteins contain N-terminal signal peptides that mediate insertion of the nascent translation products into the membrane of the endoplasmic reticulum. After membrane insertion, signal peptides typically are cleaved from the mature protein and degraded. Here, we tested whether a small hydrophobic protein selected for growth promoting activity in mammalian cells retained transforming activity while also acting as a signal peptide. We replaced the signal peptide of the PDGF beta receptor (PDGF beta R) with a previously described 29-residue artificial transmembrane protein named 9C3 that can activate the PDGF beta R in trans. We showed that a modified version of 9C3 at the N-terminus of the PDGF beta R can function as a signal peptide, as assessed by its ability to support high level expression, glycosylation, and cell surface localization of the PDGF beta R. The 9C3 signal peptide retains its ability to interact with the transmembrane domain of the PDGF beta R and cause receptor activation and cell proliferation. Cleavage of the 9C3 signal peptide from the mature receptor is not required for these activities. However, signal peptide cleavage does occur in some molecules, and the cleaved signal peptide can persist in cells and activate a co-expressed PDGF beta R in trans. Our finding that a hydrophobic sequence can display signal peptide and transforming activity suggest that some naturally occurring signal peptides may also display additional biological activities by interacting with the transmembrane domains of target proteins. (C) 2021 The Authors. Published by Elsevier Ltd.
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