ADAM12/syndecan-4 signaling promotes β1 integrin-dependent cell spreading through protein kinase Cα and RhoA

Charles Kumar Thodeti, Reidar Albrechtsen, Morten Grauslund, Meena Asmar, Christer Larsson, Yoshikazu Takada, Arthur M. Mercurio, John R. Couchman, Ulla M. Wewer

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

The ADAMs (a disintegrin and metalloprotease) comprise a large family of multidomain proteins with cell-binding and metalloprotease activities. The ADAM12 cysteine-rich domain (rADAM12-cys) supports cell attachment using syndecan-4 as a primary cell surface receptor that subsequently triggers β1, integrin-dependent cell spreading, stress fiber assembly, and focal adhesion formation. This process contrasts with cell adhesion on fibronectin, which is integrin-initiated but syndecan-4-dependent. In the present study, we investigated ADAM12/syndecan-4 signaling leading to cell spreading and stress fiber formation. We demonstrate that syndecan-4, when present in significant amounts, promotes β1 integrin-dependent cell spreading and stress fiber formation in response to rADAM12-cys. A mutant form of syndecan-4 deficient in protein kinase C (PKC)α activation or a different member of the syndecan family, syndecan-2, was unable to promote cell spreading. GF109203X and Gö6976, inhibitors of PKC, completely inhibited ADAM12/syndecan-4-induced cell spreading. Expression of syndecan-4, but not syn4ΔI, resulted in the accumulation of activated, integrins at the cell periphery in Chinese hamster ovary fil 131 cells as revealed by 12G10 staining. Further, expression of myristoylated, constitutively active PKCα resulted in β1 integrin-dependent cell spreading, but additional activation of RhoA was required to induce stress fiber formation. In summary, these data provide novel insights into syndecan-4 signaling. Syndecan-4 can promote cell spreading in a β1 integrin-dependent fashion through PKCα and RhoA, and PKCα and RhoA likely function in separate pathways.

Original languageEnglish (US)
Pages (from-to)9576-9584
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number11
DOIs
StatePublished - Mar 14 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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    Thodeti, C. K., Albrechtsen, R., Grauslund, M., Asmar, M., Larsson, C., Takada, Y., Mercurio, A. M., Couchman, J. R., & Wewer, U. M. (2003). ADAM12/syndecan-4 signaling promotes β1 integrin-dependent cell spreading through protein kinase Cα and RhoA. Journal of Biological Chemistry, 278(11), 9576-9584. https://doi.org/10.1074/jbc.M208937200