SEMA3G

SEMA3G is a secreted class-3 semaphorin that signals through neuropilin (NRP1, NRP2) and PlexinA receptors to regulate cell migration, proliferation, and differentiation across vascular, neural, metabolic, and immune contexts. In endothelial cells, BMP9/ALK1/Smad/SOX17 signaling transcriptionally induces SEMA3G, which then inhibits VEGFR2 phosphorylation to suppress VEGF-driven angiogenesis (PMID:38795838), while PPARγ directly activates the SEMA3G promoter to promote NRP2-dependent endothelial migration (PMID:25335934). SEMA3G exerts paracrine effects on neighboring cells: it activates YAP via NRP2/PlexinA1–LATS1 inhibition to drive vascular smooth muscle cell proliferation (PMID:36720439), induces c-Myc ubiquitination through a NRP2/PLXNA1–Cdc42–WWP2 cascade to suppress glioblastoma stem cell stemness (PMID:40533501), binds NRP1 on CD8⁺ T cells to function as an immune checkpoint ligand suppressing cytotoxic immunity (PMID:39652581), and promotes adipogenesis via PI3K/Akt/GSK3β and AMPK/SREBP-1c signaling (PMID:31648186). A loss-of-function SEMA3G mutation that disrupts PlexinA binding impairs GnRH neuron migration, linking SEMA3G deficiency to disorders of GnRH neuron development (PMID:32365351).

1. 2012 Medium

   The initial question of whether SEMA3G has functional relevance in tumor cell behavior was addressed by showing that overexpression in glioma cells inhibits migration and invasion through both cell-autonomous and paracrine mechanisms involving MMP2 suppression, establishing SEMA3G as a negative regulator of tumor cell motility.

   Evidence Stable overexpression in U251MG glioma cells with conditioned media transfer and Matrigel invasion assays

   PMID:22562223

   Open questions at the time

   • Single cell line; mechanism of MMP2 suppression undefined
   • No receptor identification
   • No in vivo validation
2. 2015 High

   How SEMA3G transcription is controlled and which receptor mediates its endothelial effects was resolved by demonstrating that PPARγ directly binds the SEMA3G promoter and that SEMA3G promotes endothelial migration through NRP2, establishing the first transcriptional regulator and receptor for SEMA3G.

   Evidence ChIP for PPARγ at SEMA3G promoter, reporter assay, siRNA knockdown, anti-NRP2 neutralizing antibody in HUVEC migration assay

   PMID:25335934

   Open questions at the time

   • Whether NRP2 acts alone or with a plexin co-receptor was not determined
   • Downstream signaling from NRP2 in endothelial cells not characterized
3. 2020 Medium

   Two studies expanded SEMA3G biology beyond cancer and vasculature: one showed SEMA3G promotes adipogenesis via PI3K/Akt/GSK3β and AMPK/SREBP-1c pathways in adipose and liver tissue with in vivo metabolic consequences, while another identified a human loss-of-function SEMA3G mutation disrupting PlexinA binding and GnRH neuron migration, linking SEMA3G to neuroendocrine development.

   Evidence shRNA knockdown in 3T3-L1 preadipocytes and HFD mouse model (adipogenesis); exome sequencing, homology modeling, and GnRH neuron migration assay (neuroendocrine)

   PMID:31648186 PMID:32365351

   Open questions at the time

   • Adipogenesis study from single lab without independent replication
   • GnRH study relies on structural modeling rather than direct binding measurement for PlexinA interaction
   • Whether SEMA3G signals through NRP or PlexinA in adipocytes is unknown
4. 2023 High

   The paracrine signaling axis from endothelial-derived SEMA3G to vascular smooth muscle cells was mechanistically dissected, revealing that SEMA3G acts through NRP2/PlexinA1 to inhibit LATS1 and activate YAP, driving VSMC proliferation — the first defined intracellular pathway for SEMA3G-driven proliferation.

   Evidence Recombinant SEMA3G treatment of HASMCs with receptor-specific inhibition, verteporfin (YAP inhibitor) rescue, in vivo diabetic femoral injury model

   PMID:36720439

   Open questions at the time

   • How NRP2/PlexinA1 engagement leads to LATS1 inhibition is not defined
   • Whether this pathway operates outside diabetic vascular injury is untested
5. 2024 High

   The upstream transcriptional control of SEMA3G in pulmonary endothelium and its anti-angiogenic mechanism were defined: BMP9 signals through ALK1/Smad1/Smad5 and SOX17 to upregulate SEMA3G, which inhibits VEGFR2 phosphorylation, positioning SEMA3G as an effector of the BMP9 anti-angiogenic program.

   Evidence Sequential siRNA knockdowns of BMPR2, ACTR2A, Smad1, Smad5, SOX17, and SEMA3G with VEGFR2 phosphorylation and endothelial functional assays

   PMID:38795838

   Open questions at the time

   • Direct SOX17 binding to SEMA3G promoter not confirmed by ChIP
   • Whether SEMA3G inhibits VEGFR2 through direct binding or indirect receptor crosstalk is unresolved
6. 2025 High

   SEMA3G was identified as an immune checkpoint ligand: it binds NRP1 with higher affinity than NRP2 on CD8⁺ T cells, and its genetic deletion or antibody blockade restores T-cell cytotoxicity and suppresses tumor growth, establishing a direct immunosuppressive function.

   Evidence Receptor affinity screening, CRISPR/Cas9 knockout, neutralizing antibody blockade, CD8⁺ T-cell cytotoxicity assays, in vivo tumor models

   PMID:39652581

   Open questions at the time

   • Downstream signaling in T cells upon NRP1 engagement not characterized
   • Contribution of NRP2 vs NRP1 in different immune cell subsets unclear
7. 2025 High

   The deepest mechanistic dissection of SEMA3G signaling was achieved in glioblastoma: endothelial-derived SEMA3G activates NRP2/PLXNA1 on GSCs, inactivating Cdc42 and releasing WWP2 to ubiquitinate and degrade c-Myc, thereby suppressing cancer stemness — the first complete signaling cascade from SEMA3G receptor to a transcription factor substrate.

   Evidence Co-IP, genetic Sema3G deletion in ECs, ubiquitination assays, recombinant protein treatment, in vivo GBM survival model

   PMID:40533501

   Open questions at the time

   • Whether Cdc42–WWP2 dissociation is a general mechanism downstream of all SEMA3G/PlexinA signaling or GSC-specific is unknown
   • Structural basis for SEMA3G-induced Cdc42 inactivation not defined

• Key unresolved questions include the structural basis for SEMA3G's differential receptor selectivity (NRP1 vs NRP2), how SEMA3G inhibits VEGFR2 phosphorylation (direct vs indirect), and whether the diverse downstream cascades (YAP, Cdc42/WWP2, PI3K/Akt) converge on shared proximal signaling events or represent entirely context-specific pathways.
• No crystal structure of SEMA3G–neuropilin complex
• No unified model reconciling pro-migratory and anti-migratory effects across cell types
• In vivo genetic models (conditional knockouts) in most tissue contexts are lacking