Positive regulation of cell-cell and cell-substrate adhesion by protein kinase A
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 β1 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 β1 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 β1 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 β1 integrins, and that this enzyme may be required for upregulation of cell-substrate and cell-cell adhesion.