PLXDC2

PLXDC2 is a type I transmembrane cell-surface receptor that transduces extracellular ligand cues into intracellular signaling to control cell proliferation, immune phenotype, and cancer cell behavior (PMID:25535841, PMID:39197453). It functions as a receptor for PEDF, forming dissociable homooligomers under basal conditions that are activated when PEDF binding disrupts the oligomer, with intracellular-domain residues being critical for receptor activity (PMID:25535841). A second ligand, secreted extracellular PTEN, binds PLXDC2 on macrophages and triggers JAK2-STAT1 signaling that reprograms tumor-associated macrophages from an immunosuppressive to an inflammatory state, enhancing CD8+ T and NK cell activation (PMID:39197453). In cancer, PLXDC2 promotes invadopodium formation and invasion by binding PTP1B through its intracellular region and binding cortactin through its extracellular region, sustaining elevated phospho-cortactin by preventing its dephosphorylation (PMID:15574754, PMID:35661947); PLXDC2 is itself induced downstream of c-Met/ERK1/2-ELK1 signaling to drive EMT and cancer stem cell plasticity (PMID:37089864). Its shed extracellular domain acts as a cell-non-autonomous mitogen for embryonic neural progenitors (PMID:21283688), and in microglia PLXDC2 maintains a homeostatic state via PPARγ–NF-κB signaling to limit neuroinflammation (PMID:40345569). PLXDC2 also marks hematopoietic stem cells with long-term multilineage reconstitution capacity (PMID:41372396).

1. 2004 Medium

   Identifying the first physical partner of PLXDC2 established that its extracellular region engages the actin-regulatory protein cortactin, hinting at a role in cytoskeletal/invasive processes.

   Evidence Affinity pulldown and binding-domain mapping for TEM7R (PLXDC2)

   PMID:15574754

   Open questions at the time

   • Functional consequence of the cortactin interaction not tested here
   • Single lab, no reciprocal in vivo validation
2. 2011 Medium

   Showed PLXDC2 acts cell-non-autonomously as a mitogen, localizing the proliferative activity to a cleaved/shed extracellular domain rather than full-length receptor signaling.

   Evidence In ovo electroporation in chick neural tube plus mouse neuroepithelial cultures with extracellular-domain constructs

   PMID:21283688

   Open questions at the time

   • Receptor/partner mediating the mitogenic effect on progenitors unidentified
   • Protease responsible for ectodomain shedding unknown
3. 2014 High

   Defined PLXDC2 as a bona fide PEDF receptor with a regulatory mechanism—homooligomers dissociated by ligand binding—answering how the receptor is activated.

   Evidence Reciprocal loss/gain-of-function across cellular models, oligomerization assays, intracellular-domain mutagenesis

   PMID:25535841

   Open questions at the time

   • Downstream effectors of PEDF–PLXDC2 signaling not delineated
   • Structural basis of oligomer dissociation not resolved
4. 2019 Low

   First link of PLXDC2 to coagulation-factor gene expression, suggesting a transcriptional/regulatory role beyond surface receptor function.

   Evidence siRNA knockdown in a hepatocellular carcinoma cell line with F5/F2/F10 mRNA readout

   PMID:31271701

   Open questions at the time

   • Single siRNA, single cell line, not independently confirmed
   • No mechanistic pathway connecting PLXDC2 to coagulation factor transcription
5. 2022 Medium

   Provided a mechanism for PLXDC2-driven cancer invasion by showing it sequesters PTP1B to protect phospho-cortactin, connecting the earlier cortactin interaction to invadopodia.

   Evidence Co-IP with PTP1B, knockdown/overexpression invasion assays, phospho-cortactin measurement in gastric cancer cells

   PMID:35661947

   Open questions at the time

   • Co-IP not reciprocally validated structurally
   • Whether PEDF/PTEN ligand engagement modulates the PTP1B interaction untested
6. 2023 Medium

   Placed PLXDC2 downstream of c-Met/ERK1/2-ELK1 signaling and showed it drives EMT and cancer stem cell plasticity, explaining a route to radioresistance.

   Evidence Phospho-antibody arrays, knockdown, c-Met inhibition (SU11274), EMT/CSC assays, orthotopic HNSCC model

   PMID:37089864

   Open questions at the time

   • Direct ELK1 occupancy of the PLXDC2 promoter not shown
   • Effectors mediating PLXDC2-induced EMT undefined
7. 2024 High

   Identified secreted PTEN as a second PLXDC2 ligand and mapped a JAK2-STAT1 axis that reprograms tumor-associated macrophages, establishing an immunomodulatory receptor function.

   Evidence Binding assays, intratumoral PTEN injection in mice, JAK2-STAT1 analysis, macrophage/T/NK co-cultures, anti-PD-1 combination

   PMID:39197453

   Open questions at the time

   • How a normally intracellular phosphatase becomes a secreted ligand not fully resolved
   • Relationship between PTEN and PEDF binding sites on PLXDC2 unknown
8. 2025 Medium

   Demonstrated PLXDC2 maintains microglial homeostasis via PPARγ–NF-κB signaling, defining a neuroprotective role in ischemic injury, while a complementary study linked it to Aβ phagocytosis and cytokine control.

   Evidence In vivo AAV overexpression/lentivirus knockdown in microglia with PPARγ/NF-κB readouts (stroke); BV2 overexpression with Aβ phagocytosis and cytokine assays (Alzheimer model)

   PMID:40345569 PMID:41126775

   Open questions at the time

   • Ligand driving microglial PLXDC2 signaling not identified
   • BV2 phagocytosis study is single overexpression in one cell line
   • Mechanism connecting PLXDC2 to PPARγ activation unresolved
9. 2025 Medium

   Established PLXDC2 as a surface marker of long-term reconstituting hematopoietic stem cells in both mouse and human, extending its biology to stem cell identity.

   Evidence Plxdc2-GFP knock-in reporter, transplantation assays, anti-human PLXDC2 antibody, xenograft reconstitution

   PMID:41372396

   Open questions at the time

   • Functional requirement of PLXDC2 for HSC maintenance vs. correlation as a marker not separated
   • Ligand/signaling in HSCs undefined

• How a single receptor reconciles distinct ligands (PEDF, secreted PTEN), an ectodomain-shedding mitogen activity, and tissue-specific signaling outputs (JAK2-STAT1, PPARγ-NF-κB, PTP1B/cortactin) into a unified mechanism remains unresolved.
• No structure of PLXDC2 with any ligand
• Intracellular signaling effectors of the full-length receptor incompletely mapped
• Whether the same domain mediates PEDF vs PTEN binding unknown