Syndecan-4/PAR-3 signaling regulates focal adhesion dynamics in mesenchymal cells
Author
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Valdivia Hepp, Juan
Author
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Cárdenas, Areli
Author
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Brenet, Marianne
Author
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Maldonado, Horacio
Author
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Kong, Milene
Author
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Díaz Jara, Jorge
Author
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Burridge, Keith
Author
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Schneider, Pascal
Author
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San Martín, Alejandra
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García Mata, Rafael
Author
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Quest, Andrew F. G.
Author
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Leyton, Lisette
Admission date
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2020-11-11T23:52:55Z
Available date
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2020-11-11T23:52:55Z
Publication date
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2020
Cita de ítem
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Cell Communication and Signaling (2020) 18:129
es_ES
Identifier
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10.1186/s12964-020-00629-3
Identifier
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https://repositorio.uchile.cl/handle/2250/177674
Abstract
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Background: Syndecans regulate cell migration thus having key roles in scarring and wound healing processes. Our previous results have shown that Thy-1/CD90 can engage both alpha v beta 3 integrin and Syndecan-4 expressed on the surface of astrocytes to induce cell migration. Despite a well-described role of Syndecan-4 during cell movement, information is scarce regarding specific Syndecan-4 partners involved in Thy-1/CD90-stimulated cell migration.
Methods: Mass spectrometry (MS) analysis of complexes precipitated with the Syndecan-4 cytoplasmic tail peptide was used to identify potential Syndecan-4-binding partners. The interactions found by MS were validated by immunoprecipitation and proximity ligation assays. The conducted research employed an array of genetic, biochemical and pharmacological approaches, including: PAR-3, Syndecan-4 and Tiam1 silencing, active Rac1 GEFs affinity precipitation, and video microscopy.
Results: We identified PAR-3 as a Syndecan-4-binding protein. Its interaction depended on the carboxy-terminal EFYA sequence present on Syndecan-4. In astrocytes where PAR-3 expression was reduced, Thy-1-induced cell migration and focal adhesion disassembly was impaired. This effect was associated with a sustained Focal Adhesion Kinase activation in the siRNA-PAR-3 treated cells. Our data also show that Thy-1/CD90 activates Tiam1, a PAR-3 effector. Additionally, we found that after Syndecan-4 silencing, Tiam1 activation was decreased and it was no longer recruited to the membrane. Syndecan-4/PAR-3 interaction and the alteration in focal adhesion dynamics were validated in mouse embryonic fibroblast (MEF) cells, thereby identifying this novel Syndecan-4/PAR-3 signaling complex as a general mechanism for mesenchymal cell migration involved in Thy-1/CD90 stimulation.
Conclusions: The newly identified Syndecan-4/PAR-3 signaling complex participates in Thy-1/CD90-induced focal adhesion disassembly in mesenchymal cells. The mechanism involves focal adhesion kinase dephosphorylation and Tiam1 activation downstream of Syndecan-4/PAR-3 signaling complex formation. Additionally, PAR-3 is defined here as a novel adhesome-associated component with an essential role in focal adhesion disassembly during polarized cell migration. These novel findings uncover signaling mechanisms regulating cell migration, thereby opening up new avenues for future research on Syndecan-4/PAR-3 signaling in processes such as wound healing and scarring.
es_ES
Patrocinador
dc.description.sponsorship
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDECYT
1150744
1200836
1170925
3140471
3160349
3170169
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDAP
15130011
United States Department of Health & Human Services
National Institutes of Health (NIH) - USA
HL113167
GM029860
1R21CA194776-01A1
1R15CA199101-01A1
Swiss National Science Foundation (SNSF)
31003A_176256