The heat shock protein GRP78 typically resides in the endoplasmic reticulum in normal tissues, but it has been shown to be expressed on the cell surface of several cancer cells, and some stem cells, where it can act as a signaling molecule by not-yet-fully defined mechanisms. Although cell surface GRP78 (sGRP78) has emerged as an attractive chemotherapeutic target, understanding how sGRP78 is functioning in cancer has been complicated by the fact that sGRP78 can function in a cell-context dependent manner, with a diverse array of reported binding partners, to regulate a variety of cellular responses. We had previously shown that sGRP78 was important in regulating pluripotent stem cell (PSC) functions, and hypothesized that embryonic-like mechanisms of GRP78 were critical to regulating aggressive breast cancer cell functions. Here, using proteomics we identify Dermcidin (DCD) as a novel sGRP78 binding partner common to both PSCs and breast cancer cells. We show that GRP78 and DCD cooperate to regulate stem cell and cancer cell migration that is dependent on the cell surface functions of these proteins. Finally, we identify Wnt/β-catenin signaling, a critical pathway in stem cell and cancer cell biology, as an important downstream intermediate in regulating this migration phenotype.
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This work was supported in part by an American Cancer Society Research Scholar Grant (RSG-20-022-01-CDD), a Walther Cancer Foundation Advancing Basic Cancer grant, and by grant UL1TR001108 from the Indiana Clinical and Translational Sciences Institute (to ADP). CC was supported in part by grant TL1TR001107 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. CRK was supported in part through a Hiller Family Research Fellowship. We thank the members of the D’Souza-Schorey laboratory for kindly providing valuable advice for the TOPFlash assays; Drs. Michelle Joyce, Matthew Champion, and Bill Boggess of the Notre Dame Mass Spectrometry and Proteomics Facility for proteomics; and Dr. Sara Cole of the Optical Microscopy Core, Notre Dame Integrated Imaging Facility (NDIIF), for her microscopy assistance and expertise. We thank Drs. Jonathan Kelber and Peter Gray for valuable discussions, and three anonymous reviewers for their helpful comments. We are grateful to the Gallagher Family for their generous support of stem cell research at the University of Notre Dame.
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Lager, T.W., Conner, C., Keating, C.R. et al. Cell surface GRP78 and Dermcidin cooperate to regulate breast cancer cell migration through Wnt signaling. Oncogene 40, 4050–4059 (2021). https://doi.org/10.1038/s41388-021-01821-6
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