PDZ Proteins SCRIB and DLG1 Regulate Myeloma Cell Surface CD86 Expression, Growth, and Survival

• Type of Material: Article
• Authors: Tyler Moser-Katz, Emory University; Catherine M Gavile, Emory University; Benjamin Barwick, Emory University; Kelvin P Lee, Indiana University; Lawrence Boise, Emory University
• Language: English
• Date: 2022-07-01
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, American Association for Cancer Research
• Final Published Version (URL): http://dx.doi.org/10.1158/1541-7786.MCR-21-0681
• Title of Journal or Parent Work: MOLECULAR CANCER RESEARCH
• Volume: 20
• Issue: 7
• Start Page: 1122
• End Page: 1136
• Grant/Funding Information: This work was supported by R01 CA121044 (K.P.L.), R01 CA192844 (L.H.B.), and Paula and Rodger Riney Foundation (L.H.B.). B.G.B. was supported by Developmental Funds from Winship Cancer Institute of Emory University, post-doctoral fellowship PF-17-109-1-TBG from the American Cancer Society, a Research Fellow Award from the MMRF, and American Society of Hematology Scholar Award. Research reported in this publication was supported in part by the Pediatrics/Winship Flow Cytometry Core of Winship Cancer Institute of Emory University, Children’s Healthcare of Atlanta and NIH/NCI under award number P30CA138292.; Research reported in this publication was also supported in part by the Emory Integrated Genomics Core (EIGC), Emory Integrated Proteomics Core, and Integrated Cellular Imaging shared resources of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: MCL-1 DEPENDENCE; CD28; RECEPTOR; Oncology; Science & Technology; ACTIVATION; CYTOPLASMIC TAIL; LOCALIZATION; MULTIPLE-MYELOMA; Cell Biology; SUSTAINED ANTIBODY-RESPONSES; BINDING; B-CELL; Life Sciences & Biomedicine

Abstract

Despite advances in the treatment of multiple myeloma in the past decades, the disease remains incurable, and understanding signals and molecules that can control myeloma growth and survival are important for the development of novel therapeutic strategies. One such molecule, CD86, regulates multiple myeloma cell survival via its interaction with CD28 and signaling through its cytoplasmic tail. Although the CD86 cytoplasmic tail has been shown to be involved in drug resistance and can induce molecular changes in multiple myeloma cells, its function has been largely unexplored. Here, we show that CD86 cytoplasmic tail has a role in trafficking CD86 to the cell surface. This is due in part to a PDZbinding motif at its C-terminus which is important for proper trafficking from the Golgi apparatus. BioID analysis revealed 10 PDZ domain-containing proteins proximal to CD86 cytoplasmic tail in myeloma cells. Among them, we found the planar cell polarity proteins, SCRIB and DLG1, are important for proper CD86 surface expression and the growth and survival of myeloma cells. These findings indicate a mechanism by which myeloma cells confer cellular survival and drug resistance and indicate a possible motif to target for therapeutic gain.