Involvement of the MEKK1 signaling pathway in the regulation of epicardial cell behavior by hyaluronan.
During embryonic development, cells comprising the outermost layer of the heart or epicardium play a critical role in the formation of the coronary vasculature. Thus, uncovering the molecular mechanisms that govern epicardial cell behavior is imperative to better understand the etiology of cardiovascular diseases. In this study, we investigated the function of hyaluronan (HA), a major component of the extracellular matrix, in the modulation of epicardial signaling. We show that stimulation of epicardial cells with high molecular weight HA (HMW-HA) promotes the association of MEKK1 with the HA receptor CD44 and induces MEKK1 phosphorylation. This leads to the activation of two distinct pathways, one ERK-dependent and another NFkappaB-dependent. Furthermore, HMW-HA stimulates epicardial cells to differentiate and invade, as suggested by increased vimentin expression and enhanced invasion through a collagen matrix. Blockade of CD44, transfection with a kinase-inactive MEKK1 construct or the use of ERK1/2 and NFkappaB inhibitors significantly abrogates the invasive response to HMW-HA. Together, these findings suggest an important role for HA in the regulation of epicardial cell fate via activation of MEKK1 signaling cascades.
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, Arizona, USA.
Evisabel A
EA
Craig
Patti
P
Parker
Anita F
AF
Austin
Joey V
JV
Barnett
Todd D
TD
Camenisch
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000494:pharmacology*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D010496:Pericardium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D027602:Serum Response Element; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
D018960:Hyaluronan Receptors; D016328:NF-kappa B; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D006820:Hyaluronic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048728:MAP Kinase Kinase Kinase 1