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Laminin-sulfatide binding initiates basement membrane assembly and enables receptor signaling in Schwann cells and fibroblasts.

Li S, Liquari P, McKee KK, Harrison D, Patel R, Lee S, Yurchenco PD - J. Cell Biol. (2005)

Bottom Line: This glycolipid anchors Lm-1 and -2 to SC surfaces by binding to their LG domains and enables basement membrane (BM) assembly.Revealingly, non-BM-forming fibroblasts become competent for BM assembly when sulfatides are intercalated into their cell surfaces.Collectively, our findings suggest that sulfated glycolipids are key Lm anchors that determine which cell surfaces can assemble Lms to initiate BM assembly and DG- and integrin-mediated signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.

ABSTRACT
Endoneurial laminins (Lms), beta1-integrins, and dystroglycan (DG) are important for Schwann cell (SC) ensheathment and myelination of axons. We now show that SC expression of galactosyl-sulfatide, a Lm-binding glycolipid, precedes that of Lms in developing nerves. This glycolipid anchors Lm-1 and -2 to SC surfaces by binding to their LG domains and enables basement membrane (BM) assembly. Revealingly, non-BM-forming fibroblasts become competent for BM assembly when sulfatides are intercalated into their cell surfaces. Assembly is characterized by coalescence of sulfatide, DG, and c-Src into a Lm-associated complex; by DG-dependent recruitment of utrophin and Src activation; and by integrin-dependent focal adhesion kinase phosphorylation. Collectively, our findings suggest that sulfated glycolipids are key Lm anchors that determine which cell surfaces can assemble Lms to initiate BM assembly and DG- and integrin-mediated signaling.

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Working model distinguishing Lm anchorage from signaling. Lm (blue) binds to sulfatides (red lipids in membrane) through its LG domains and polymerizes to create a nascent BM scaffolding that captures and binds to nidogen and type IV collagen. These self-assembly steps are distinguished from those of the binding of the BM to DG (orange) and β1-integrins (β1, blue), the former being directly or indirectly bound to c-Src/Fyn. Src/Fyn becomes activated through tyrosine phosphorylation and may translocate to the nucleus. Lm assembly recruits cytoskeletal utrophin to β-DG, which, in turn, can bind to the actin cytoskeleton. β1-integrin mediates FAK tyrosine phosphorylation.
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fig10: Working model distinguishing Lm anchorage from signaling. Lm (blue) binds to sulfatides (red lipids in membrane) through its LG domains and polymerizes to create a nascent BM scaffolding that captures and binds to nidogen and type IV collagen. These self-assembly steps are distinguished from those of the binding of the BM to DG (orange) and β1-integrins (β1, blue), the former being directly or indirectly bound to c-Src/Fyn. Src/Fyn becomes activated through tyrosine phosphorylation and may translocate to the nucleus. Lm assembly recruits cytoskeletal utrophin to β-DG, which, in turn, can bind to the actin cytoskeleton. β1-integrin mediates FAK tyrosine phosphorylation.

Mentions: The evidence from both SCs and sulfatide-treated fibroblasts constitutes the first demonstration of a critical mediator of Lm anchorage (Fig. 10). Interpreting the new cell findings in the context of the biophysical evidence (Kalb and Engel, 1991; Yurchenco and Cheng, 1993), we propose that sulfated glycolipids such as gal-sulfatide facilitate Lm polymerization by specifically binding to the Lm–LG domains and increasing the local Lm concentration at the cell surface. This initial ECM then binds to nidogens, type IV collagens, and other BM components to complete BM assembly. Signaling functions, on the other hand, are reserved for transmembrane protein receptors whose binding to the Lm scaffolding and/or attached BM components is enabled by anchorage and Lm polymerization. Two receptor classes implicated in SCs, and mirrored in the sulfatide-loaded fibroblasts, are DG and β1-integrins. The signals detected in response to DG and integrin were c-Src/Fyn and FAK tyrosine phosphorylation, respectively; the former is implicated in protecting the cells from apoptosis. In addition, utrophin, which can bind to both β-DG and F-actin, was recruited to the BM zone in a step that required DG and its ECM interaction. Thus, BM assembly consists of its self-assembly, initiated by Lm polymerization and anchorage through sulfated glycolipids, and its signal transduction, which is enabled by assembly and is mediated through integrin and DG receptor interactions.


Laminin-sulfatide binding initiates basement membrane assembly and enables receptor signaling in Schwann cells and fibroblasts.

Li S, Liquari P, McKee KK, Harrison D, Patel R, Lee S, Yurchenco PD - J. Cell Biol. (2005)

Working model distinguishing Lm anchorage from signaling. Lm (blue) binds to sulfatides (red lipids in membrane) through its LG domains and polymerizes to create a nascent BM scaffolding that captures and binds to nidogen and type IV collagen. These self-assembly steps are distinguished from those of the binding of the BM to DG (orange) and β1-integrins (β1, blue), the former being directly or indirectly bound to c-Src/Fyn. Src/Fyn becomes activated through tyrosine phosphorylation and may translocate to the nucleus. Lm assembly recruits cytoskeletal utrophin to β-DG, which, in turn, can bind to the actin cytoskeleton. β1-integrin mediates FAK tyrosine phosphorylation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171891&req=5

fig10: Working model distinguishing Lm anchorage from signaling. Lm (blue) binds to sulfatides (red lipids in membrane) through its LG domains and polymerizes to create a nascent BM scaffolding that captures and binds to nidogen and type IV collagen. These self-assembly steps are distinguished from those of the binding of the BM to DG (orange) and β1-integrins (β1, blue), the former being directly or indirectly bound to c-Src/Fyn. Src/Fyn becomes activated through tyrosine phosphorylation and may translocate to the nucleus. Lm assembly recruits cytoskeletal utrophin to β-DG, which, in turn, can bind to the actin cytoskeleton. β1-integrin mediates FAK tyrosine phosphorylation.
Mentions: The evidence from both SCs and sulfatide-treated fibroblasts constitutes the first demonstration of a critical mediator of Lm anchorage (Fig. 10). Interpreting the new cell findings in the context of the biophysical evidence (Kalb and Engel, 1991; Yurchenco and Cheng, 1993), we propose that sulfated glycolipids such as gal-sulfatide facilitate Lm polymerization by specifically binding to the Lm–LG domains and increasing the local Lm concentration at the cell surface. This initial ECM then binds to nidogens, type IV collagens, and other BM components to complete BM assembly. Signaling functions, on the other hand, are reserved for transmembrane protein receptors whose binding to the Lm scaffolding and/or attached BM components is enabled by anchorage and Lm polymerization. Two receptor classes implicated in SCs, and mirrored in the sulfatide-loaded fibroblasts, are DG and β1-integrins. The signals detected in response to DG and integrin were c-Src/Fyn and FAK tyrosine phosphorylation, respectively; the former is implicated in protecting the cells from apoptosis. In addition, utrophin, which can bind to both β-DG and F-actin, was recruited to the BM zone in a step that required DG and its ECM interaction. Thus, BM assembly consists of its self-assembly, initiated by Lm polymerization and anchorage through sulfated glycolipids, and its signal transduction, which is enabled by assembly and is mediated through integrin and DG receptor interactions.

Bottom Line: This glycolipid anchors Lm-1 and -2 to SC surfaces by binding to their LG domains and enables basement membrane (BM) assembly.Revealingly, non-BM-forming fibroblasts become competent for BM assembly when sulfatides are intercalated into their cell surfaces.Collectively, our findings suggest that sulfated glycolipids are key Lm anchors that determine which cell surfaces can assemble Lms to initiate BM assembly and DG- and integrin-mediated signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.

ABSTRACT
Endoneurial laminins (Lms), beta1-integrins, and dystroglycan (DG) are important for Schwann cell (SC) ensheathment and myelination of axons. We now show that SC expression of galactosyl-sulfatide, a Lm-binding glycolipid, precedes that of Lms in developing nerves. This glycolipid anchors Lm-1 and -2 to SC surfaces by binding to their LG domains and enables basement membrane (BM) assembly. Revealingly, non-BM-forming fibroblasts become competent for BM assembly when sulfatides are intercalated into their cell surfaces. Assembly is characterized by coalescence of sulfatide, DG, and c-Src into a Lm-associated complex; by DG-dependent recruitment of utrophin and Src activation; and by integrin-dependent focal adhesion kinase phosphorylation. Collectively, our findings suggest that sulfated glycolipids are key Lm anchors that determine which cell surfaces can assemble Lms to initiate BM assembly and DG- and integrin-mediated signaling.

Show MeSH
Related in: MedlinePlus