PLXNB2

PLXNB2 is a transmembrane semaphorin-family receptor that transduces ligand cues into control of cytoskeletal mechanics and cell differentiation across neural development, tissue fibrosis, and cancer. In neural progenitors, PLXNB2 maintains cortical tension through actomyosin contractility, establishing a mechanical barrier against premature differentiation; its loss lowers cortical tension and triggers premature cell-cycle exit, accelerated neuronal commitment, progenitor depletion, and neuroepithelial disorganization. Biallelic loss-of-function variants in PLXNB2 cause an autosomal recessive syndrome of amelogenesis imperfecta, sensorineural hearing loss, and variable intellectual disability, with receptor expression in differentiating ameloblasts linking PLXNB2 to enamel formation (PMID:38458752). As a signaling receptor, PLXNB2 engages SEMA4D secreted by macrophages to drive fibrogenic activation of hepatic stellate cells, and acts as a glial receptor in astrocytes and microglia that shapes amygdala-mediated stress responses (PMID:36325348) and an H3K18-lactylation-driven neuroprotective microglial program after ischemic stroke (PMID:40835170). In cancer, a G842C gain-of-function mutation sustains tumor stem cell self-renewal and invasiveness via basal EGFR phosphorylation, and PLXNB2 sits upstream of AKT/ERK1/2 signaling in ovarian cancer cells where it is controlled by miRNA regulatory axes (PMID:36722641, PMID:30054097).

1. 2018 Medium

   Established PLXNB2 as a node upstream of pro-proliferative kinase signaling, answering whether the receptor feeds canonical growth pathways in cancer.

   Evidence Luciferase 3'UTR validation of miR-126-3p targeting plus siRNA knockdown with phospho-AKT/ERK1/2 readout in ovarian cancer cells

   PMID:30054097

   Open questions at the time

   • Does not identify the ligand driving AKT/ERK1/2 activation
   • Single cell-line context; no in vivo confirmation of the signaling axis
2. 2021 Medium

   Extended the regulatory understanding of PLXNB2 by placing its expression under a circRNA/miRNA sponge axis controlling tumorigenic behavior.

   Evidence Dual-luciferase and RIP assays for circ_0013958/miR-637/PLXNB2 plus knockdown and xenograft assays in ovarian cancer

   PMID:34367233

   Open questions at the time

   • Regulation is transcript-level; does not address receptor signaling mechanism
   • No structural or ligand-binding detail
3. 2022 Medium

   Defined a glial, non-neuronal function for PLXNB2, addressing whether the receptor acts in CNS cell types governing behavior.

   Evidence Intra-amygdaloid functional-blocking monoclonal antibody with behavioral, volumetric MRI, and microglial morphology readouts in mouse

   PMID:36325348

   Open questions at the time

   • No genetic KO confirmation of the antibody phenotype
   • Ligand and downstream signaling in glia not identified
4. 2023 High

   Showed that a specific gain-of-function mutation reprograms PLXNB2 into an oncogenic driver coupled to EGFR, distinguishing mutant from wild-type receptor function.

   Evidence Mutant-selective shRNA knockdown, lentiviral gene transfer, xenograft tumorigenesis, EGFR phospho-immunoblot, and EGFR inhibitor treatment in CUP stem cells

   PMID:36722641

   Open questions at the time

   • Mechanism by which G842C activates EGFR is not resolved
   • Whether wild-type PLXNB2 couples to EGFR under any condition is unclear
5. 2024 High

   Connected PLXNB2 to human Mendelian disease, answering whether loss of the receptor produces a defined developmental syndrome.

   Evidence Exome/genome sequencing with Sanger segregation across six families and mouse ameloblast expression analysis

   PMID:38458752

   Open questions at the time

   • Cellular mechanism linking PLXNB2 loss to enamel and inner-ear defects not established
   • Variant-specific functional consequences not assayed
6. 2024 Low

   Proposed PLXNB2 as a stromal receptor for tumor-derived angiogenin, addressing tumor-stromal paracrine signaling.

   Evidence Single-cell RNA-seq of paired human colon/CRC tissue with CellChat ligand-receptor inference

   PMID:38295715

   Open questions at the time

   • Purely computational inference; no biochemical validation of PLXNB2-angiogenin binding
   • No functional assay of the proposed signaling
7. 2025 Medium

   Identified the mechanical mechanism by which PLXNB2 controls neural progenitor fate, linking the receptor to cortical tension and differentiation timing.

   Evidence CRISPR KO in cerebral organoids with cortical tension measurement and cell-cycle/differentiation marker analysis (preprint)

   Open questions at the time

   • Preprint, not peer-reviewed
   • Ligand and downstream actomyosin effectors not defined
   • Direct mechanistic link to patient intellectual disability is correlative
8. 2025 Medium

   Established an epigenetically driven, ligand-coupled PLXNB2 program in microglia, defining a neuroprotective role in ischemia.

   Evidence MCAO mouse model with H3K18la manipulation and microglia-specific Plxnb2 inhibition and outcome measures

   PMID:40835170

   Open questions at the time

   • Downstream microglial signaling from PLXNB2 not resolved
   • Single-lab study
9. 2025 Medium

   Defined a SEMA4D-PLXNB2 ligand-receptor axis driving fibrogenic stellate cell activation, naming a direct ligand for the receptor in tissue fibrosis.

   Evidence Single-cell fixed RNA profiling of TAA-induced mouse liver fibrosis with in vivo SEMA4D blockade (preprint)

   Open questions at the time

   • Preprint, single lab
   • Direct SEMA4D-PLXNB2 binding not biochemically demonstrated here
   • Downstream signaling in HSCs not characterized

• How PLXNB2 ligand engagement is mechanistically transduced into cytoskeletal, EGFR, and AKT/ERK outputs across its different cell-type contexts remains unresolved.
• No structural model of ligand-receptor or receptor-EGFR coupling
• Unified downstream signaling logic across neural, glial, fibrotic, and cancer contexts is undefined