Calautti Enzo, Grossi Maddalena, Mammucari Cristina, Aoyama Yumi, Pirro Maria, Ono Yoshitaka, Li Jie, Dotto G Paolo
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129.
J Cell Biol. 2002 Jan 7;156(1):137-48. doi: 10.1083/jcb.200105140. Epub 2002 Jan 3.
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.
Rho GTP酶和Fyn酪氨酸激酶此前被认为参与角质形成细胞间细胞黏附的正向调控。在此，我们表明Rho和Fyn沿相同的信号通路发挥作用。在分化的角质形成细胞中内源性Rho活性增加，且其对于Fyn激酶激活以及β-连环蛋白和γ-连环蛋白酪氨酸磷酸化增加均是必需的，而这与角质形成细胞间细胞黏附的建立相关。相反，组成型活性Rho的表达足以通过酪氨酸激酶和Fyn依赖的机制促进细胞间黏附，触发Fyn激酶激活，并诱导β-连环蛋白、γ-连环蛋白和p120连环蛋白的酪氨酸磷酸化。活化Rho对细胞间黏附的正向作用并非由与丝氨酸/苏氨酸PRK2/PKN激酶结合缺陷的活化Rho突变体所诱导。内源性PRK2激酶活性随角质形成细胞分化而增加，并且与活化Rho一样，增加的PRK2活性促进角质形成细胞间细胞黏附，并诱导β-连环蛋白、γ-连环蛋白的酪氨酸磷酸化以及Fyn激酶激活。因此，这些发现揭示了Fyn作为Rho在调控角质形成细胞间细胞黏附中的下游介质的新作用，并表明PRK2激酶（一种直接的Rho效应器）是Rho和Fyn激活之间的联系。
