{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRAPH1, which encodes the adaptor protein lamellipodin (Lpd), is emerging as a key regulator of actin cytoskeletal dynamics and cell migration. By recruiting actin‐modulating proteins such as Ena/VASP, Lpd facilitates lamellipodia formation at the leading edge of migrating cells. In addition, its spatial targeting is fine‐tuned by regulatory molecules like profilin1 that restrict lamellipodin’s accumulation where actin polymerization is most active."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and biochemical studies have revealed that lamellipodin contains Ras-association and pleckstrin homology (PH) domains that mediate its low-affinity binding to phosphoinositides – notably PI(3,4)P₂. This interaction governs its recruitment to plasma membrane subdomains, where it orchestrates the assembly of multiprotein complexes that regulate actin filament elongation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn an unexpected twist linking cytoskeletal dynamics to enzymatic assembly, proline-rich peptides derived from lamellipodin have been isolated from native butyrylcholinesterase (BChE) tetramers. These peptides drive the oligomerization of BChE into a stable tetrameric configuration, and genetic studies support the hypothesis that the CHE2 locus corresponds to RAPH1. Thus, lamellipodin not only modulates cell motility but also contributes to the stabilization of key plasma proteins in the circulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in actin assembly, lamellipodin participates in multiple aspects of membrane dynamics. It forms part of a molecular complex with talin and integrins that promotes the formation of dynamic “sticky fingers” for sensing the extracellular matrix, and it facilitates clathrin-mediated endocytosis of receptors such as the epidermal growth factor receptor (EGFR) by associating with proteins like Mena and endophilin. In specialized cell types such as podocytes, lamellipodin is recruited by nephrin to coordinate actin remodeling necessary for lamellipodia formation. Moreover, the conserved function of its Drosophila ortholog, pico, underscores lamellipodin’s role in coupling growth factor signaling to transcriptional responses via changes in actin dynamics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent studies have also implicated RAPH1 in oncogenesis. Alterations in the RAPH1 gene, including amplifications and deletions in breast carcinoma samples, suggest that dysregulation of lamellipodin may affect tumor progression. Notably, a nuclear isoform (RAPH1-i3) has been shown to interact with FOXQ1 to activate signaling pathways such as STAT3, thereby promoting cell proliferation, migration, and radioresistance in triple-negative breast cancer, and positioning RAPH1 as a potential therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "He Li, Lawrence M Schopfer, Patrick Masson, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Profilin1 regulates PI(3,4)P2 and lamellipodin accumulation at the leading edge thus influencing motility of MDA-MB-231 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1002309107"}], "href": "https://doi.org/10.1073/pnas.1002309107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21115820"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21115820"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yu-Chung Chang, Hao Zhang, Mark L Brennan, et al. 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