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Published on: February 21, 2018
PDZ Proteins SCRIB and DLG1 Regulate Myeloma Cell Surface CD86 Expression, Growth, and Survival
Tyler Moser-Katz1, Catherine M Gavile1, Benjamin G Barwick1
1Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
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 PDZ-binding 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.
Implications:
These findings demonstrate the importance of proper trafficking of CD86 to the cell surface in myeloma cell survival and may provide a new therapeutic target in this disease.
Insights
The CD86 protein
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Multiple myeloma remains incurable despite treatment advances.
- CD86 regulates myeloma cell survival through its cytoplasmic tail, impacting drug resistance.
- The precise function of the CD86 cytoplasmic tail in myeloma is largely unknown.
Purpose of the Study:
- To investigate the role of the CD86 cytoplasmic tail in multiple myeloma cell survival and drug resistance.
- To identify proteins interacting with the CD86 cytoplasmic tail and their function in myeloma.
Main Methods:
- BioID analysis to identify proximal proteins to the CD86 cytoplasmic tail.
- Investigating the role of PDZ-binding motifs in CD86 trafficking.
- Assessing the impact of SCRIB and DLG1 on CD86 surface expression and myeloma cell growth.
Main Results:
- The CD86 cytoplasmic tail, via a C-terminal PDZ-binding motif, is crucial for CD86 trafficking from the Golgi to the cell surface.
- BioID identified 10 PDZ domain-containing proteins interacting with the CD86 cytoplasmic tail.
- SCRIB and DLG1 were found to be essential for CD86 surface expression, myeloma cell growth, and survival.
Conclusions:
- The CD86 cytoplasmic tail plays a critical role in trafficking CD86 to the cell surface, influencing myeloma cell survival and drug resistance.
- Interactions with PDZ proteins like SCRIB and DLG1 are key to CD86's function in myeloma.
- Targeting the CD86 cytoplasmic tail motif offers a potential therapeutic strategy for multiple myeloma.
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