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We have identified Cleft Lip and Palate Transmembrane 1\u2010Like (CLPTM1L)\/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related mediator of cytoprotection in pancreatic cancer. We recently demonstrated that CLPTM1L is highly expressed in pancreatic ductal adenocarcinoma and associated with poor outcome. Furthermore, we have discovered that CLPTM1L interacts with phosphoinositol\u20103\u2010kinase\u2010alpha at the tumor cell surface and causes up\u2010regulation of Bcl\u2010xL and pAkt mediated survival signaling. Here, we demonstrate surface relocalization and survival signaling by CLPTM1L triggered by endoplasmic reticular (ER) stress. We demonstrate the interaction of CLPTM1L with the central ER stress survival mediator, Glucose Regulated Protein 78 (GRP78)\/Binding Immunoglobulin Protein (BiP) and PI3K\u2010alpha \/p110\u03b1. This interaction and surface relocalization of CLPTM1L and GRP78 is induced by ER stress, including that caused by treatment with gemcitabine. We demonstrate that the extracellular loop of CLPTM1L is required for gemcitabine resistance and interaction with GRP78. This interaction and the chemoresistance effect conferred by this pathway is targetable with our recently developed inhibitory CLPTM1L antibodies, which may represent novel modalities of chemosensitization and treatment of pancreatic adenocarcinoma. Anchorage independent growth, GRP78\u2010mediated chemoresistance, and Akt phosphorylation were abrogated by inhibition of CLPTM1L. These findings demonstrate a novel and potentially targetable mechanism of cytoprotection and chemoresistance in pancreatic tumors.<\/jats:p>","DOI":"10.1002\/ijc.32012","type":"journal-article","created":{"date-parts":[[2018,11,23]],"date-time":"2018-11-23T10:59:03Z","timestamp":1542970743000},"page":"1367-1378","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["CLPTM1L\/CRR9 ectodomain interaction with GRP78 at the cell surface signals for survival and chemoresistance upon ER stress in pancreatic adenocarcinoma cells"],"prefix":"10.1002","volume":"144","author":[{"given":"William R.","family":"Clarke","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laufey","family":"Amundadottir","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division 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