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© The Rockefeller University Press, 0021-9525/1998//1449 $5.00
The Journal of Cell Biology, Volume 141, Number 6, , 1998 1449-1465

Articles

Tyrosine Phosphorylation and Src Family Kinases Control Keratinocyte Cell–Cell Adhesion



Enzo Calautti*, Sara Cabodi*,{ddagger}, Paul L. Stein§, Mechthild Hatzfeld||, Nancy Kedersha, and G. Paolo Dotto*

* Cutaneous Biology Research Center, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts 02129; {ddagger} Department of Biology, Genetics and Medical Chemistry, University of Torino, Torino, Italy 10126; § Wistar Institute, Philadelphia, Pennsylvania 19104; || Molecular Biology Group, Medical Faculty of the University of Halle, Halle, Germany 06097; and Division of Rheumatology and Immunology, Brigham and Woman's Hospital, Boston, Massachusetts 02115

In their progression from the basal to upper differentiated layers of the epidermis, keratinocytes undergo significant structural changes, including establishment of close intercellular contacts. An important but so far unexplored question is how these early structural events are related to the biochemical pathways that trigger differentiation. We show here that β-catenin, {gamma}-catenin/plakoglobin, and p120-Cas are all significantly tyrosine phosphorylated in primary mouse keratinocytes induced to differentiate by calcium, with a time course similar to that of cell junction formation. Together with these changes, there is an increased association of {alpha}-catenin and p120-Cas with E-cadherin, which is prevented by tyrosine kinase inhibition. Treatment of E-cadherin complexes with tyrosine-specific phosphatase reveals that the strength of {alpha}-catenin association is directly dependent on tyrosine phosphorylation. In parallel with the biochemical effects, tyrosine kinase inhibition suppresses formation of cell adhesive structures, and causes a significant reduction in adhesive strength of differentiating keratinocytes. The Fyn tyrosine kinase colocalizes with E-cadherin at the cell membrane in calcium-treated keratinocytes. Consistent with an involvement of this kinase, fyn-deficient keratinocytes have strongly decreased tyrosine phosphorylation levels of β- and {gamma}-catenins and p120-Cas, and structural and functional abnormalities in cell adhesion similar to those caused by tyrosine kinase inhibitors. Whereas skin of fyn–/– mice appears normal, skin of mice with a disruption in both the fyn and src genes shows intrinsically reduced tyrosine phosphorylation of β-catenin, strongly decreased p120-Cas levels, and important structural changes consistent with impaired keratinocyte cell adhesion. Thus, unlike what has been proposed for oncogene-transformed or mitogenically stimulated cells, in differentiating keratinocytes tyrosine phosphorylation plays a positive role in control of cell adhesion, and this regulatory function appears to be important both in vitro and in vivo.

Address all correspondence to G.P. Dotto, Cutaneous Biology Research Center, Building 149, 13th Street, Charlestown, MA 02129. Tel.: (617) 724-9538. Fax: (617) 724-9572. E-mail: Paolo_Dotto{at}CBRC.MGH.Harvard.edu


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