Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling.
Transforming growth factor-beta (TGFbeta) regulates the activation state of the endothelium via two opposing type I receptor/Smad pathways. Activin receptor-like kinase-1 (ALK1) induces Smad1/5 phosphorylation, leading to an increase in endothelial cell proliferation and migration, while ALK5 promotes Smad2/3 activation and inhibits both processes. Here, we report that ALK5 is important for TGFbeta/ALK1 signaling; endothelial cells lacking ALK5 are deficient in TGFbeta/ALK1-induced responses. More specifically, we show that ALK5 mediates a TGFbeta-dependent recruitment of ALK1 into a TGFbeta receptor complex and that the ALK5 kinase activity is required for optimal ALK1 activation. TGFbeta type II receptor is also required for ALK1 activation by TGFbeta. Interestingly, ALK1 not only induces a biological response opposite to that of ALK5 but also directly antagonizes ALK5/Smad signaling.
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Marie José
MJ
Goumans
Gudrun
G
Valdimarsdottir
Susumu
S
Itoh
Franck
F
Lebrin
Jonas
J
Larsson
Christine
C
Mummery
Stefan
S
Karlsson
Peter
P
ten Dijke
D030201:Activin Receptors, Type I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000818:Animals; D019556:COS Cells; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1; D046911:Macromolecular Substances; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D004268:DNA-Binding Proteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D046911:Macromolecular Substances; D010750:Phosphoproteins; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human