Endoglin inhibits prostate cancer motility via activation of the ALK2-Smad1 pathway.
Endoglin is a transforming growth factor beta (TGFbeta) superfamily auxiliary receptor. We had previously shown that it suppressed prostate cancer (PCa) cell motility, and that its expression was lost during PCa progression. The mechanism by which endoglin inhibits PCa cell motility is unknown. Here we demonstrate that endoglin abrogates TGFbeta-mediated cell motility, but does not alter cell surface binding of TGFbeta. By measuring Smad-specific phosphorylation and Smad-responsive promoter activity, endoglin was shown to constitutively activate Smad1, with little-to-no effect upon Smad3. Knockdown of Smad1 increased motility and abrogated endoglin's effects. As type I activin receptor-like kinases (ALKs) are necessary for Smad activation, we went on to show that knockdown of ALK2, but not TGFbetaRI (ALK5), abrogated endoglin-mediated decreases in cell motility and constitutively active ALK2 was sufficient to restore a low-motility phenotype in endoglin deficient cells. These findings provide the first evidence that endoglin decreases PCa cell motility through activation of the ALK2-Smad1 pathway.
Craft
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Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, Northwestern University and the Robert H Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
Romero
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Vary
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Bergan
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D030201:Activin Receptors, Type I / Q000502:physiology*; D015703:Antigens, CD / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D000071063:Endoglin; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051898:Smad1 Protein / Q000502:physiology*
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C497399:SMAD1 protein, human; D051898:Smad1 Protein; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I