MARCH Proteins Mediate Responses to Antitumor Antibodies

Abstract

CD98, which is required for the rapid proliferation of both normal and cancer cells, and MET, the hepatocyte growth factor receptor, are potential targets for therapeutic antitumor Abs. In this study, we report that the antiproliferative activity of a prototype anti-CD98 Ab, UM7F8, is due to Ab-induced membrane-associated ring CH (MARCH) E3 ubiquitin ligase-mediated ubiquitination and downregulation of cell surface CD98. MARCH1-mediated ubiquitination of CD98 is required for UM7F8's capacity to reduce CD98 surface expression and its capacity to inhibit the proliferation of murine T cells. Similarly, CD98 ubiquitination is required for UM7F8's capacity to block the colony-forming ability of murine leukemia-initiating cells. To test the potential generality of the paradigm that MARCH E3 ligases can mediate the antiproliferative response to antitumor Abs, we examined the potential effects of MARCH proteins on responses to emibetuzumab, an anti-MET Ab currently in clinical trials for various cancers. We report that MET surface expression is reduced by MARCH1, 4, or 8-mediated ubiquitination and that emibetuzumab-induced MET ubiquitination contributes to its capacity to downregulate MET and inhibit human tumor cell proliferation. Thus, MARCH E3 ligases can act as cofactors for antitumor Abs that target cell surface proteins, suggesting that the MARCH protein repertoire of cells is a determinant of their response to such Abs.

Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain

“…S10B), suggesting that R8H283 is unlikely to inhibit the function of CD98hc–light chain complexes as amino acid transporters ( 28 , 30 ). Unlike the anti-CD98hc mAb UM7F8, which limits cell proliferation by reducing CD98hc abundance at the cell surface through the Membrane associated ring-CH-type finger (MARCH1) or MARCH8 ubiquitin ligase–dependent mechanism ( 31 ), R8H283 did not mediate a reduction in CD98hc abundance at the cell surface upon binding to Ramos B cell lymphoma cells (fig. S10, C and D).…”

Fibronectin, DHPS and SLC3A2 Signaling Cooperate to Control Tumor Spheroid Growth, Subcellular eIF5A1/2 Distribution and CDK4/6 Inhibitor Resistance

“…Thus, we tested a previously reported antibody-induced ubiquitin ligase-mediated SLC3A2 downregulation protocol in triple negative breast cancer (TNBC) cells that employs a mouse monoclonal anti-human SLC3A2 antibody (clone UM7F8, IgG1) combined with a goat antimouse IgG F(ab′)2 antibody [37]. This approach achieved a significant UM7F8-dependent SLC3A2 downregulation in MDA-MB-468 and MCF10CA1h cell models of TNBC (Figure 2B-C).…”

Membrane-associated RING-CH 7 inhibits stem-like capacities of bladder cancer cells by interacting with nucleotide-binding oligomerization domain containing 1

“…Members of the MARCH family exhibit diversity and participate in multiple physiological functions, including sperm formation, membrane transfer, and lipid synthesis [ 20 ]. Emerging evidence suggests that MARCH family proteins are involved in tumor progression [ 21 ]. Overexpression of MARCH1 promotes ovarian cancer progression through the regulation of NF-κB and Wnt/β-catenin signaling pathways [ 22 ] while MARCH1 overexpression in oral squamous cell carcinoma promotes tumor progression through regulation of the PH domain and leucine-rich repeat protein phosphatase (PHLPP) 2 [ 23 ].…”