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Fyn tyrosine kinase is a downstream mediator of Rho/PRK2 function in keratinocyte cell-cell adhesion
Enzo Calautti1, Maddalena Grossi, Cristina Mammucari
1Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129.
Abstract:
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 beta- and gamma-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 beta- and gamma-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 beta- and gamma-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.
Insights
Rho GTPase and Fyn tyrosine kinase control keratinocyte cell-cell adhesion via a shared pathway. Rho activation promotes adhesion by activating Fyn kinase and phosphorylating catenins, with PRK2 kinase linking Rho to Fyn signaling.
Area of Science:
- Cell biology
- Biochemistry
- Dermatology
Background:
- Rho GTPase and Fyn tyrosine kinase are known regulators of keratinocyte cell-cell adhesion.
- The precise signaling pathway connecting Rho and Fyn in this context is not fully understood.
Purpose of the Study:
- To elucidate the signaling pathway by which Rho GTPase and Fyn tyrosine kinase regulate keratinocyte cell-cell adhesion.
- To investigate the role of PRK2 kinase in mediating the effects of Rho on Fyn activation and cell adhesion.
Main Methods:
- Studied endogenous Rho activity during keratinocyte differentiation.
- Utilized constitutively active Rho mutants to assess effects on cell adhesion and signaling.
- Examined PRK2 kinase activity in differentiating keratinocytes.
- Assessed tyrosine phosphorylation of beta-catenin, gamma-catenin, and p120ctn.
Main Results:
- Rho activity increases during keratinocyte differentiation and is essential for Fyn kinase activation and beta-/gamma-catenin phosphorylation.
- Activated Rho promotes cell-cell adhesion, Fyn activation, and catenin phosphorylation in a Fyn-dependent manner.
- Rho's pro-adhesion effects are dependent on PRK2/PKN kinase binding; PRK2 activity increases with differentiation and mimics Rho's effects.
Conclusions:
- Rho GTPase and Fyn tyrosine kinase function sequentially in a common pathway controlling keratinocyte cell-cell adhesion.
- Fyn acts as a downstream mediator of Rho signaling in this process.
- PRK2 kinase serves as a crucial link connecting Rho activation to Fyn activation and subsequent modulation of cell-cell adhesion.
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