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Positive regulation of cell-cell and cell-substrate adhesion by protein kinase A

Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA

*Author for correspondence (e-mail: akiyama{at}niehs.nih.gov)

Accepted June 1, 2001

Integrin receptor activation is an important regulatory mechanism for cell-substrate and cell-cell adhesion. In this study, we explore a signaling pathway activated by mAb 12G10, an antibody that can activate ß₁ integrins and induce integrin-mediated cell-cell and cell-substrate adhesion. We have found that the cAMP-dependent protein kinase (PKA) is required for both mAb 12G10-induced cell-cell and cell-substrate adhesion of HT-1080 cells. Binding of mAb 12G10 to ß₁ integrins stimulates an increase in intracellular cAMP levels and PKA activity, and a concomitant shift in the localization of the PKA type II regulatory subunits from the cytoplasm to areas where integrins expressing the 12G10 epitope are located. MAb 12G10-induced cell-cell adhesion was mimicked by a combination of clustering ß₁ integrins and elevating PKA activity with Sp-adenosine-3',5'-cyclic monophosphorothioate or forskolin. We also show that two processes required for HT-1080 cell-cell adhesion, integrin clustering and F-actin polymerization are both dependent on PKA. Taken together, our data suggest that PKA plays a key role in the signaling pathway, resulting from activation of ß₁ integrins, and that this enzyme may be required for upregulation of cell-substrate and cell-cell adhesion.

Key words: Integrin activation, Cell-cell adhesion, cAMP, PKA, F-actin, Signal transduction

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