PLXDC2 - A Multifunctional Receptor in Development, Immunity and Cancer

Plexin domain containing 2 (PLXDC2) is a nidogen/plexin homology transmembrane protein encoded by PLXDC2. PLXDC2 is specifically expressed on the surface of macrophages but not neutrophils, T cells, or NK cells. PLXDC2 is an emerging transmembrane receptor implicated in the regulation of angiogenesis, cellular migration, tissue remodeling, and tumor-associated signaling. Originally identified through its expression in endothelial and neural tissues, PLXDC2 has gained increasing attention for its role in orchestrating complex cellular communication networks that influence development, regeneration, and disease progression.

PLXDC2 has several functions: i) in the brain, it is involved in the proliferation and differentiation of neural progenitors during the development of the nervous system; ii) in the immune system, PLXDC2 on macrophages binds to secreted PTEN (phosphatase and tensin homolog) to sequentially activate JAK2-STAT1 signaling, reprogram macrophages and drive antitumor immunity and is specifically expressed and elevated in human pancreatic cancer tissue and serum. 

PLXDC2, together with its homolog PLXDC1, seems to be also the receptor for pigment epithelium-derived factor (PEDF) in endothelial cells. Recently, it has been shown that PLXDC2 is highly expressed in human and mouse HSCs derived from both cord blood and bone marrow and PLXDC2 can be used as a new key marker to enrich both mouse and human HSCs using flow cytometry. It was also described as a transmembrane mediator of endothelial-immune crosstalk and metabolic control and has been identified to have anti-inflammatory, anti-angiogenic and antioxidant functions. PLXDC2 is a biomarker of cancers, with aberrant expression of PLXDC2 in different types of cancers and potentially seems to be a biomarker for pre-diabetic patients, IBD and rheumatoid arthritis (RA).

A study from the lab of Prof. Toshio Kitamura (University of Tokyo, Japan) described in the Journal Communications Biology that the protein PLXDC2 is highly expressed in human and mouse HSCs derived from both cord blood and bone marrow, and PLXDC2 can be used as a new key marker to enrich both human and mouse HSCs using flow cytometry. The study shows that the use of both PLXDC2 and CD150 membrane proteins is sufficient for the isolation of functional HSCs without any additional markers. PLXDC2 in combination with CD150 is a new, very efficient, and easy protocol to highly purify mouse and human functional HSCs compared with the conventional multi-antibody combination (CD34+CD38-CD90+CD45RA-CD49f+) that results in only ~10% functional HSCs.

Unlike traditional intracellular immunometabolic regulators, PLXDC2 acts at the interface of immune-stromal communication, functioning as a transmembrane receptor that integrates metabolic and inflammatory cues across multiple tissue types. PLXDC2 is a transmembrane receptor expressed on the cell surface of macrophages, dendritic and specific mesenchymal and epithelial cells whose activation shifts cellular metabolism and reduces oxidative stress to modulate pro-inflammatory and regulatory cell programs. Mechanistically, PLXDC2 activation appears to engage signaling cascades that modulate both redox balance and macrophage metabolic programming, including decreased glycolytic flux and increased mitochondrial integrity. 

AdipoGen Life Sciences offers a unique panel of PLXDC2 research reagents, including Recombinant Proteins, Antibodies and ELISA Kits.

Literature References: 

1. Identification of a Binding Partner for the Endothelial Cell Surface Proteins TEM7 and TEM7R: A. Nanda, et al.; Cancer Res. 64, 8507 (2004)
2. Plxdc2 Is a Mitogen for Neural Progenitors: S.F.C. Miller-Delaney, et al.; PLoS One 6, e14565 (2011)
3. Identification of PLXDC1 and PLXDC2 as the transmembrane receptors for the multifunctional factor PEDF: G. Cheng, et al.; eLife 23, e05401 (2014)
4. Plexin domain containing protein 2 is more expressed within the invasive area of human colorectal cancer tissues: Y. Hamada, et al.; Hum. Cell. 34, 1580 (2021)
5. Secreted PTEN binds PLXDC2 on macrophages to drive antitumor immunity and tumor suppression: C. Zhang, et al.; Develop. Cell 59, 3072 (2025)
6. Plexin Domain Containing 2, a Protein Specifically Expressed and Elevated in Human Pancreatic Cancer Tissue and Serum, Influences Cell Proliferation by Correlating with Cortactin: J. Tsuboi, et al.; Cancer Med. 14, e71459 (2025)
7. Prospective isolation of mouse and human hematopoietic stem cells using PLXDC2: Y. Tanaka, et al.; Commun. Biol. 9, 20 (2025)
8. Immunometabolism as a New Bimodal Therapeutic Concept in inflammatory Bowel Disease and ImmuneMediated Inflammatory Disorders: V. Solitano, et al.; Inflamm. Bowel Dis. 32, 803 (2026)

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