| Structural highlights
Function
GPC3_MOUSE Cell surface proteoglycan (By similarity). Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins (PubMed:18477453, PubMed:23665349). Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation (PubMed:18477453). Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands (By similarity). Positively regulates the non-canonical Wnt signaling pathway (PubMed:15537637). Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (PubMed:23665349). Inhibits the dipeptidyl peptidase activity of DPP4 (By similarity). Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4 (PubMed:10964473). Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis (PubMed:11180950). Required for coronary vascular development (PubMed:19733558). Plays a role in regulating cell movements during gastrulation (By similarity).[UniProtKB:P51654][UniProtKB:Q6V9Y8][1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.
GPC3-Unc5 receptor complex structure and role in cell migration.,Akkermans O, Delloye-Bourgeois C, Peregrina C, Carrasquero-Ordaz M, Kokolaki M, Berbeira-Santana M, Chavent M, Reynaud F, Raj R, Agirre J, Aksu M, White ES, Lowe E, Ben Amar D, Zaballa S, Huo J, Pakos I, McCubbin PTN, Comoletti D, Owens RJ, Robinson CV, Castellani V, Del Toro D, Seiradake E Cell. 2022 Oct 13;185(21):3931-3949.e26. doi: 10.1016/j.cell.2022.09.025. PMID:36240740[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Paine-Saunders S, Viviano BL, Zupicich J, Skarnes WC, Saunders S. glypican-3 controls cellular responses to Bmp4 in limb patterning and skeletal development. Dev Biol. 2000 Sep 1;225(1):179-87. doi: 10.1006/dbio.2000.9831. PMID:10964473 doi:http://dx.doi.org/10.1006/dbio.2000.9831
- ↑ Grisaru S, Cano-Gauci D, Tee J, Filmus J, Rosenblum ND. Glypican-3 modulates BMP- and FGF-mediated effects during renal branching morphogenesis. Dev Biol. 2001 Mar 1;231(1):31-46. doi: 10.1006/dbio.2000.0127. PMID:11180950 doi:http://dx.doi.org/10.1006/dbio.2000.0127
- ↑ Song HH, Shi W, Xiang YY, Filmus J. The loss of glypican-3 induces alterations in Wnt signaling. J Biol Chem. 2005 Jan 21;280(3):2116-25. doi: 10.1074/jbc.M410090200. Epub 2004, Nov 10. PMID:15537637 doi:http://dx.doi.org/10.1074/jbc.M410090200
- ↑ Capurro MI, Xu P, Shi W, Li F, Jia A, Filmus J. Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding. Dev Cell. 2008 May;14(5):700-11. doi: 10.1016/j.devcel.2008.03.006. PMID:18477453 doi:http://dx.doi.org/10.1016/j.devcel.2008.03.006
- ↑ Ng A, Wong M, Viviano B, Erlich JM, Alba G, Pflederer C, Jay PY, Saunders S. Loss of glypican-3 function causes growth factor-dependent defects in cardiac and coronary vascular development. Dev Biol. 2009 Nov 1;335(1):208-15. doi: 10.1016/j.ydbio.2009.08.029. Epub 2009, Sep 4. PMID:19733558 doi:http://dx.doi.org/10.1016/j.ydbio.2009.08.029
- ↑ Bhave VS, Mars W, Donthamsetty S, Zhang X, Tan L, Luo J, Bowen WC, Michalopoulos GK. Regulation of liver growth by glypican 3, CD81, hedgehog, and Hhex. Am J Pathol. 2013 Jul;183(1):153-9. doi: 10.1016/j.ajpath.2013.03.013. Epub 2013 , May 8. PMID:23665349 doi:http://dx.doi.org/10.1016/j.ajpath.2013.03.013
- ↑ Akkermans O, Delloye-Bourgeois C, Peregrina C, Carrasquero-Ordaz M, Kokolaki M, Berbeira-Santana M, Chavent M, Reynaud F, Raj R, Agirre J, Aksu M, White ES, Lowe E, Ben Amar D, Zaballa S, Huo J, Pakos I, McCubbin PTN, Comoletti D, Owens RJ, Robinson CV, Castellani V, Del Toro D, Seiradake E. GPC3-Unc5 receptor complex structure and role in cell migration. Cell. 2022 Oct 13;185(21):3931-3949.e26. doi: 10.1016/j.cell.2022.09.025. PMID:36240740 doi:http://dx.doi.org/10.1016/j.cell.2022.09.025
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