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STAT5a activation mediates the epithelial to mesenchymal transition induced by oncogenic RhoA
Salvador Aznar Benitah1, Pilar F Valerón, Hallgeir Rui
1Instituto de Investigaciones Biomédicas, CSIC, Madrid, Spain.
Abstract:
The involvement of Rho GTPases in signal transduction pathways leading to transcription activation is one of the major roles of this family of GTPases. Thus, the identification of transcription factors regulated by Rho GTPases and the understanding of the mechanisms of their activation and its biological outcome are of great interest. Here, we provide evidence that Rho GTPases modulate Stat5a, a transcription factor of the family of signal transducers and activators of transcription. RhoA triggers tyrosine phosphorylation (Y696) of Stat5a via a JAK2-dependent mechanism and promotes DNA-binding activity of Stat5a. Tyrosine phosphorylation of Stat5a is also stimulated physiologically by lysophosphatidic acid (LPA) in a Rho-dependent manner. Simultaneously, RhoA reduces serine phosphorylation of Stat5a at both serine residues S726 and S780, resulting in a further increase of activity as defined by mutagenesis experiments. Furthermore, serine dephosphorylation of Stat5a by RhoA does not take place by down-modulation of either JNK1, MEK1, or p38 MAP kinases, as determined by transfection experiments or chemical inhibition of both MEK1, p38, and JNK serine kinases. Thus, RhoA regulates Stat5a via tyrosine phosphorylation and via a yet to be determined novel down-modulating pathway that involves serine dephosphorylation. Finally, we provide evidence for a role of Stat5a in RhoA-induced epithelial-to-mesenchymal transition with concomitant increase in vimentin expression, E-cadherin down-regulation, and cell motility.
Insights
Rho GTPases, like RhoA, regulate the transcription factor Stat5a by controlling its phosphorylation. This modulation impacts Stat5a activity and its role in cell motility and epithelial-to-mesenchymal transition.
Area of Science:
- Molecular Biology
- Cell Signaling
Background:
- Rho GTPases are key regulators of signal transduction pathways.
- Understanding transcription factor regulation by Rho GTPases is crucial for deciphering cellular processes.
Purpose of the Study:
- To investigate the role of Rho GTPases in modulating the activity of the transcription factor Stat5a.
- To elucidate the mechanisms by which RhoA influences Stat5a phosphorylation and function.
Main Methods:
- Utilized transfection experiments and chemical inhibition to study kinase activity.
- Performed mutagenesis experiments to assess Stat5a activity.
- Analyzed Stat5a phosphorylation at specific tyrosine and serine residues.
Main Results:
- RhoA induces JAK2-dependent tyrosine phosphorylation (Y696) of Stat5a, enhancing its DNA-binding activity.
- RhoA reduces Stat5a serine phosphorylation (S726, S780), further increasing its activity.
- Stat5a plays a role in RhoA-induced epithelial-to-mesenchymal transition, affecting vimentin and E-cadherin expression and cell motility.
Conclusions:
- RhoA regulates Stat5a activity through a novel mechanism involving both tyrosine phosphorylation and serine dephosphorylation.
- Stat5a is implicated in RhoA-mediated cellular processes like epithelial-to-mesenchymal transition and cell motility.