ADAM12/syndecan-4 signaling promotes beta 1 integrin-dependent cell spreading through protein kinase Calpha and RhoA.

Research output: Contribution to journalJournal articleResearchpeer-review

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

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 beta(1) 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 beta(1) 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)alpha 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 syn4DeltaI, resulted in the accumulation of activated beta(1) integrins at the cell periphery in Chinese hamster ovary beta1 cells as revealed by 12G10 staining. Further, expression of myristoylated, constitutively active PKCalpha resulted in beta(1) 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 beta(1) integrin-dependent fashion through PKCalpha and RhoA, and PKCalpha and RhoA likely function in separate pathways.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume278
Issue number11
Pages (from-to)9576-84
Number of pages8
ISSN0021-9258
DOIs
Publication statusPublished - 2002

Bibliographical note

Keywords: ADAM Proteins; Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antigens, CD29; CHO Cells; Cell Adhesion; Cell Movement; Cricetinae; Cysteine; DNA, Complementary; Humans; Immunohistochemistry; Membrane Proteins; Metalloendopeptidases; Microscopy, Fluorescence; Microscopy, Phase-Contrast; Models, Biological; Molecular Sequence Data; Muscle Proteins; Protein Kinase C; Protein Kinase C-alpha; Protein Structure, Tertiary; Rats; Sequence Homology, Amino Acid; Signal Transduction; Transfection; rhoA GTP-Binding Protein

ID: 8462490