ΔNp63α regulates Erk signaling via MKP3 to inhibit cancer metastasis.
ΔNp63α regulates Erk signaling via MKP3 to inhibit cancer metastasis.
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p53家族成员p63的表达减少已被认为在癌症转移中起致病作用。在这里，我们发现Δ Np 63 α，主要的p63亚型，在细胞迁移，侵袭和癌症转移的调节中起着重要作用。我们确定MAP激酶磷酸酶3（MKP 3）是介导这些效应所需的Δ Np 63 α的下游靶点。我们发现Δ Np 63 α通过MKP 3调节癌细胞和非转化细胞中的细胞外信号调节蛋白激酶1和2（Erk 1/2）活性。我们进一步表明，外源性Δ Np 63 α抑制细胞侵袭，并依赖于MKP 3的上调来抑制。相反，内源性pan-p63消融导致细胞迁移和侵袭增加，这可以通过单独重新引入Δ Np 63 α亚型而不是其他亚型来逆转。有趣的是，这些作用需要Erk 2，而不是Erk 1的表达，并可以通过强制MKP 3的表达来挽救。此外，侵袭性癌症中MKP 3表达降低，并且p63表达降低增加体内转移频率。综上所述，这些结果表明Δ Np 63 α通过MKP 3抑制Erk 2信号传导在预防癌症转移中起重要作用。
Reduced expression of the p53 family member p63 has been suggested to play a causative role in cancer metastasis. Here we show that ΔNp63α, the predominant p63 isoform, plays a major role in regulation of cell migration, invasion, and cancer metastasis. We identified MAP Kinase Phosphatase 3 (MKP3) as a downstream target of ΔNp63α that is required for mediating these effects. We show that ΔNp63α regulates Extracellular Signal-Regulated Protein Kinase 1 and 2 (Erk1/2) activity via MKP3 in both cancer and non-transformed cells. We further show that exogenous ΔNp63α inhibits cell invasion and is dependent on MKP3 up-regulation for repression. Conversely, endogenous pan-p63 ablation results in increased cell migration and invasion, which can be reverted by reintroducing the ΔNp63α isoform alone, but not by other isoforms. Interestingly, these effects require Erk2, but not Erk1 expression, and can be rescued by enforced MKP3 expression. Moreover, MKP3 expression is reduced in invasive cancers, and reduced p63 expression increases metastatic frequency in vivo. Taken together, these results suggest an important role for ΔNp63α in preventing cancer metastasis by inhibition of Erk2 signaling via MKP3.