Activin receptor-like kinase 1 inhibits human microvascular endothelial cell migration: potential roles for JNK and ERK.
Activin receptor-like kinase 1 (ALK1) is an endothelial-specific type I receptor of the TGFbeta receptor family that is implicated in angiogenesis and in the pathogenesis of the vascular disease, hereditary hemorrhagic telangiectasia (HHT). In the absence of a specific ligand, ALK1 cellular functions have been mainly studied through the use of a constitutively active form of this receptor (ALK1ca) and are still debated. We previously reported that ALK1ca inhibits proliferation and migration of human endothelial cells suggesting that ALK1 plays an important role in the maturation phase of angiogenesis (Lamouille et al., 2002, Blood 100: 4495-4501). In the present work, we further analyzed the role of ALK1 in the migration of human dermal microvascular endothelial cell (HMVEC-d) and observed that silencing endogenous ALK1 expression with siRNAs accelerates endothelial cell migration in the wound assay. Further, we demonstrate that ALK1-induced inhibition of migration is Smad-independent. Using a panel of kinase inhibitors, we found that HMVEC-d wound closure was completely inhibited by a JNK inhibitor and to a lower degree by an ERK kinase inhibitor. Further, HMVEC-d wounding induced activation of both JNK and ERK, and these were inhibited by ALK1ca expression. Taken together, these results support a significant role for ALK1 as a negative regulator of endothelial cell migration and suggest the implication of JNK and ERK as mediators of this effect.
David
Laurent
L
Institut National de la Santé et de la Recherche Médicale, U878, Grenoble, France.
Mallet
Christine
C
Vailhé
Bruno
B
Lamouille
Samy
S
Feige
Jean-Jacques
JJ
Bailly
Sabine
S
D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008833:Microcirculation / Q000033:anatomy & histology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D051785:Smad Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II