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The multiverse of CD46 and oncologic interactions
M. Kathryn Liszewski, John P. Atkinson
M. Kathryn Liszewski, John P. Atkinson
Published May 1, 2025
Citation Information: J Clin Invest. 2025;135(9):e188355. https://doi.org/10.1172/JCI188355.
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The multiverse of CD46 and oncologic interactions

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Abstract

Initially identified as a regulator of complement activation on host cells, the known roles of CD46 (membrane cofactor protein [MCP]) have expanded. We now know that this ancient molecule is expressed on almost all nucleated cells as a family of four predominant isoforms. It also is involved in human reproduction, modulation of T cell activation and immunoinflammatory effector functions, autophagy, and the newly identified intracellular complement system (complosome). CD46 is also known as a “pathogen” magnet, being a port of entry for at least seven bacteria and five viruses. Moreover, CD46 has recently emerged as a key player in cancer biology. Numerous studies provide evidence of the association among elevated CD46 expression, malignant transformation, and metastasizing potential. These features, along with its roles as pathogen receptor, have made CD46 a target for cancer therapeutics. Thus, modified viral vectors (such as strains of adenovirus and measles virus) targeting CD46 currently are being exploited against a wide range of cancers. Another oncologic treatment utilizes a CD46-targeting human mAb as an antibody-drug conjugate. Herein, we review CD46 and its “multiverse” of cancer interactions.

Authors

M. Kathryn Liszewski, John P. Atkinson

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Figure 1

Genomic organization of CD46.

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Genomic organization of CD46.
The alternatively spliced CD46 gene lies a...
The alternatively spliced CD46 gene lies at 1q32 and consists of 14 exons and 13 introns for a minimum length of approximately 43 kb. The protein domains, exon number, and approximate sizes (in kb) are shown. Exons are represented by vertical lines on the protein domain, and exon lengths are not to scale. The protein domains include 5′ untranslated area and signal peptide (5′UT/SP); complement control protein modules (CCP1, CCP2a, CCP2b, CCP3, and CCP4 modules); alternatively spliced exons coding for segments enriched in serines, threonines, and prolines (STP-A, -B, and -C); segment of undefined function (UND); two exons that code for the transmembrane domain (TM), TM-A and TM-B-ANC, which also codes for the intracytoplasmic anchor (ANC); and alternatively spliced cytoplasmic tail 1 (CYT-1) and cytoplasmic tail 2 and 3′ untranslated region (CYT-2/3′UT). Adapted with permission from Annual Review of Immunology (11).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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