QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: E02-08-0454v1 14/1/40    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Benitah, S. A. Articles by Lacal, J. C. Search for Related Content PubMed PubMed Citation Articles by Benitah, S. A. Articles by Lacal, J. C.

Vol. 14, Issue 1, 40-53, January 2003

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

Salvador Aznar Benitah,^§* Pilar F. Valerón,^§* Hallgeir Rui, and Juan Carlos Lacal^§

 ^§Instituto de Investigaciones Biomédicas, CSIC, Madrid, Spain, and  Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20829

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.

---

^* These two authors contributed equally to this work.

Corresponding author. E-mail address: jclacal{at}iib.uam.es.

---

Molecular Biology of the Cell
Vol. 14, 40-53, January 2003
Copyright © 2003 by The American Society for Cell Biology

This article has been cited by other articles:

				V. Kundumani-Sridharan, D. Wang, M. Karpurapu, Z. Liu, C. Zhang, N. Dronadula, and G. N. Rao Suppression of Activation of Signal Transducer and Activator of Transcription-5B Signaling in the Vessel Wall Reduces Balloon Injury-Induced Neointima Formation Am. J. Pathol., October 1, 2007; 171(4): 1381 - 1394. [Abstract] [Full Text] [PDF]

				T. K. Lee, K. Man, R. T.P. Poon, C. M. Lo, A. P. Yuen, I. O. Ng, K. T. Ng, W. Leonard, and S. T. Fan Signal Transducers and Activators of Transcription 5b Activation Enhances Hepatocellular Carcinoma Aggressiveness through Induction of Epithelial-Mesenchymal Transition. Cancer Res., October 15, 2006; 66(20): 9948 - 9956. [Abstract] [Full Text] [PDF]

				N. Akhtar and C. H. Streuli Rac1 links integrin-mediated adhesion to the control of lactational differentiation in mammary epithelia J. Cell Biol., June 5, 2006; 173(5): 781 - 793. [Abstract] [Full Text] [PDF]

				A. Woods, G. Wang, and F. Beier RhoA/ROCK Signaling Regulates Sox9 Expression and Actin Organization during Chondrogenesis J. Biol. Chem., March 25, 2005; 280(12): 11626 - 11634. [Abstract] [Full Text] [PDF]

				C. V. Clevenger Roles and Regulation of Stat Family Transcription Factors in Human Breast Cancer Am. J. Pathol., November 1, 2004; 165(5): 1449 - 1460. [Abstract] [Full Text] [PDF]

				L. Ling and P. E. Lobie RhoA/ROCK Activation by Growth Hormone Abrogates p300/Histone Deacetylase 6 Repression of Stat5-mediated Transcription J. Biol. Chem., July 30, 2004; 279(31): 32737 - 32750. [Abstract] [Full Text] [PDF]