The Rho GTPase and Fyn tyrosine kinase have been implicated previously in positive control of keratinocyte cell–cell adhesion. Here, we show that Rho and Fyn operate along the same signaling pathway. Endogenous Rho activity increases in differentiating keratinocytes and is required for both Fyn kinase activation and increased tyrosine phosphorylation of β- and γ-catenin, which is associated with the establishment of keratinocyte cell–cell adhesion. Conversely, expression of constitutive active Rho is sufficient to promote cell–cell adhesion through a tyrosine kinase- and Fyn-dependent mechanism, trigger Fyn kinase activation, and induce tyrosine phosphorylation of β- and γ-catenin and p120ctn. The positive effects of activated Rho on cell–cell adhesion are not induced by an activated Rho mutant with defective binding to the serine/threonine PRK2/PKN kinases. Endogenous PRK2 kinase activity increases with keratinocyte differentiation, and, like activated Rho, increased PRK2 activity promotes keratinocyte cell–cell adhesion and induces tyrosine phosphorylation of β- and γ-catenin and Fyn kinase activation. Thus, these findings reveal a novel role of Fyn as a downstream mediator of Rho in control of keratinocyte cell–cell adhesion and implicate the PRK2 kinase, a direct Rho effector, as a link between Rho and Fyn activation.

Mammals generate external coloration via dedicated pigment-producing cells but arrange pigment into patterns through mechanisms largely unknown. Here, using mice as models, we show that patterns ultimately emanate from dedicated pigment-receiving cells. These pigment recipients are epithelial cells that recruit melanocytes to their position in the skin and induce the transfer of melanin. We identify Foxn1 (a transcription factor) as an activator of this "pigment recipient phenotype" and Fgf2 (a growth factor and Foxn1 target) as a signal released by recipients. When Foxn1 - and thus dedicated recipients - are redistributed in the skin, new patterns of pigmentation develop, suggesting a mechanism for the evolution of coloration. We conclude that recipients provide a cutaneous template or blueprint that instructs melanocytes where to place pigment. As Foxn1 and Fgf2 also modulate epithelial growth and differentiation, the Foxn1 pathway should serve as a nexus coordinating cell division, differentiation, and pigmentation.

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