title: ΔNp63α regulates Erk signaling via MKP3 to inhibit cancer metastasis.
abstract: 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 mitogen-activated protein (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 kinases 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 upregulation 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.
authors.affiliation: 1] Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA [2] Center of Growth, Metabolism and Aging, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
authors.forename: J
authors.initials: J
authors.lastname: Bergholz
authors.affiliation: Center of Growth, Metabolism and Aging, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Walsh
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rai
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: M Y
authors.initials: MY
authors.lastname: Sherman
authors.affiliation: 1] Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA [2] Center of Growth, Metabolism and Aging, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
authors.forename: Z-X Jim
authors.initials: ZX
authors.lastname: Xiao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D054642:Dual Specificity Phosphatase 6 / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D014157:Transcription Factors / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6