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 beta(1) 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 beta(1) 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 beta(1) 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 beta(1) integrins, and that this enzyme may be required for upregulation of cell-substrate and cell-cell adhesion.
Whittard
J D
JD
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Akiyama
S K
SK
D000199:Actins / Q000187:drug effects / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology*; D000242:Cyclic AMP / Q000819:agonists / Q000378:metabolism*; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005354:Fibrosarcoma / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000378:metabolism
D000199:Actins; D000911:Antibodies, Monoclonal; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D019012:Integrin beta1; C517819:PRKAR2A protein, human; C517837:PRKAR2B protein, human; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases