The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus.
GTPases of the Rho family are transducers of extracellular signals and control cellular processes such as organization of the actin cytoskeleton, motility, adhesion and gene regulation. The Rho signalling pathway is activated, for example, by bioactive sphingolipids such as sphingosine-1-phosphate (SPP) or by overexpression of Rho family members in tumorigenesis and metastases. Here, we show that stimulation of the Rho signalling pathway induces translocation of the transcriptional LIM-only coactivator FHL2 to the nucleus and subsequent activation of FHL2- and androgen receptor-dependent genes. Interestingly, prostate tumours overexpress Rho GTPases and display altered cellular localization of FHL2 concomitant with tumour dedifferentiation. SPP-induced FHL2 activation is mediated by Rho GTPases, but not by the GTPases Cdc42, Rac1 or Ras, and depends on Rho-kinase. In addition, Rho signalling influences other transcriptional coactivators, thus pointing to a general regulatory role for Rho GTPases in cofactor function. In summary, our data propose a yet undescribed signalling pathway in which the coactivator FHL2 acts as a novel molecular transmitter of the Rho signalling pathway, thereby integrating extracellular cues into altered gene expression.
Müller
Judith M
JM
Universitäts-Frauenklinik und Zentrum für Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, D-79106 Freiburg, Germany.
Metzger
Eric
E
Greschik
Holger
H
Bosserhoff
Anja-Katrin
AK
Mercep
Luka
L
Buettner
Reinhard
R
Schüle
Roland
R
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D060850:LIM-Homeodomain Proteins; D051379:Mice; D009124:Muscle Proteins; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
C105987:FHL2 protein, human; C491382:Fhl2 protein, mouse; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D019204:GTP-Binding Proteins