MKK3 modulates JNK-dependent cell migration and invasion

Cell Death Dis. 2019 Feb 15;10(3):149. doi: 10.1038/s41419-019-1350-6.


The c-Jun N-terminal kinase (JNK) pathway plays essential roles in regulating a variety of physiological processes including cell migration and invasion. To identify critical factors that regulate JNK-dependent cell migration, we carried out a genetic screen in Drosophila based on the loss-of-cell polarity-triggered cell migration in the wing epithelia, and identified MKK3 licorne (lic) as an essential regulator of JNK-mediated cell migration and invasion. We found that loss of lic suppressed ptc > scrib-IR or ptc > Egr triggered cell migration in the wing epithelia, and Rasv12/lgl-/- induced tumor invasion in the eye discs. In addition, ectopic expression of Lic is sufficient to induce JNK-mediated but p38-independent cell migration, and cooperate with oncogenic Ras to promote tumor invasion. Consistently, Lic is able to activate JNK signaling by phosphorylating JNK, which up-regulates the matrix metalloproteinase MMP1 and integrin, characteristics of epithelial-mesenchymal transition (EMT). Moreover, lic is required for physiological JNK-mediate cell migration in thorax development. Finally, expression of human MKK3 in Drosophila is able to initiate JNK-mediated cell migration, cooperates with oncogenic Ras to trigger tumor invasion, and rescue loss-of-lic induced thorax closure defect. As previous studies suggest that MKK3 specifically phosphorylates and activates p38MAPK, our data provide the first in vivo evidence that MKK3 regulates JNK-dependent cell migration and invasion, a process evolutionarily conserved from flies to human.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Movement / genetics*
  • Cell Polarity / genetics
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Epithelial-Mesenchymal Transition / genetics
  • Evolution, Molecular
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Integrin beta Chains / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MAP Kinase Kinase 3 / genetics
  • MAP Kinase Kinase 3 / metabolism*
  • MAP Kinase Signaling System / genetics*
  • Matrix Metalloproteinase 1 / metabolism
  • Neoplasm Invasiveness / genetics
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*


  • Drosophila Proteins
  • Integrin beta Chains
  • Protein Kinases
  • lic protein, Drosophila
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3
  • MAP2K3 protein, human
  • Matrix Metalloproteinase 1