Regulation of cell surface proteins by CMTM family members

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Acute kidney injury is frequent complication of severe human disease. The early adaptive responses are poorly understood since it is difficult to visualize the repair processes that occur immediately after an injury. Using the zebrafish pronephros injury model, we identified several molecules that play an essential role in the migratory repair response that ensues immediately after an injury. EpCAM, a cancer-associated adhesion molecule, is up-regulated in cells participating in the repair process. Affinity-purification in combination with mass spectrometry revealed that EpCAM interacts with the CMTM family member CMTM6. CMTM4 and CMTM6 have recently been identified as regulators of PD-L1, which allows tumor cells to escape an anti-tumor directed immune response. We found that CMTM4 and CMTM6 are predominantly expressed in the zebrafish pronpehros and the posterior lateral line primordium (pLLP). Depletion of zebrafish cmtm4 resulted in defective pLLP migration and intracellular accumulation of Cxcr4b, suggesting that CMTM proteins are more broadly involved in the trafficking of cell surface proteins. Since both EpCAM and CXCR4 have been implicated in tumor invasion and metastasis, we propose to characterize the molecular functions of CMTM4 and CMTM6, emphasizing their role in cell migration and repair responses. Specifically, we want to 1) determine the impact of CMTM proteins on protein trafficking and intracellular signaling, 2) determine the impact of CMTM proteins on cellular programs, and 3) determine the role of CMTMs in controlling surface receptor-dependent programs in vivo. Together, these aims will elucidate the molecular functions of CMTM4/6, define their role in the regulation of cell surface receptor trafficking, and determine whether these molecules play a role in cell migration, repair and tumor metastasis.