{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPLXND1 is a key transmembrane receptor that mediates semaphorin‐dependent guidance cues during vascular development. In the developing retina, for example, neuron‐derived Sema3E binds PLXND1 on endothelial cells to activate downstream Rho GTPases, counteracting VEGF‐induced filopodia formation and thereby normalizing angiogenic directionality. Similarly, in adult and tumor‐induced angiogenesis the activation of PLXND1 leads to rapid disassembly of integrin-mediated adhesions and retraction of endothelial tip cell projections. Quantitative approaches have further illuminated how Sema3E–PLXND1 signaling induces endothelial collapse, underscoring its central role in orchestrating capillary patterning and vessel regression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n\nPLXND1 also plays complex roles in cancer. In metastatic tumor cells its activation by Sema3E can potentiate invasive behavior through non‐canonical signaling that enhances epithelial-to-mesenchymal transition (EMT) and cell motility, in part via transactivation of oncogenic kinases. In some tumors, however, PLXND1 functions as a dependence receptor that triggers apoptosis in the absence of ligand engagement, and binding of Sema3E rescues tumor cells from cell death. These seemingly paradoxical functions have been highlighted in studies of melanoma, ovarian carcinoma, and glioblastoma, and are reviewed as potential avenues for targeted therapy. Collectively, PLXND1 expression and its ligand interactions appear to modulate both tumor progression and vascular remodeling in cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "12"}]}, {"type": "t", "text": "\n\nIn developmental contexts, PLXND1 is crucial for proper organogenesis and neural patterning. De novo mutations in PLXND1 have been identified in patients with Möbius syndrome, where perturbed facial branchiomotor development is observed. In the cardiovascular system, mutations that disrupt the intracellular catalytic domain of PLXND1 are associated with congenital defects such as truncus arteriosus and anomalous pulmonary venous return, while its regulated expression influences synapse formation in the developing neocortex. Such findings underscore the receptor’s indispensable role in guiding cellular migrations and structural assembly during embryogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "17"}]}, {"type": "t", "text": "\n\nBeyond its roles in development and tumor biology, PLXND1 contributes to metabolic regulation and cell–cell signaling through distinct intracellular pathways. In zebrafish and humans, PLXND1 modulates visceral adipose tissue growth and insulin sensitivity, linking it to body fat distribution and type 2 diabetes. In endothelial cells, intracellular sorting of PLXND1 via its interaction with the adaptor GIPC1 directs receptor recycling and R-Ras inactivation, while signaling through effectors such as SH3BP1 fine-tunes Rac1 activity. Moreover, PLXND1 can mediate responses to alternative ligands such as Sema4A, influencing fibroblast contractility and T-cell differentiation, highlighting its diverse context-dependent functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yoko Fukushima, Mitsuhiro Okada, Hiroshi Kataoka, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01652-09"}], "href": "https://doi.org/10.1128/MCB.01652-09"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20385769"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20385769"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Atsuko Sakurai, Xiaoying Jian, Charity J Lee, et al. 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