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J. Biol. Chem., Vol. 281, Issue 35, 25110-25123, September 1, 2006

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Endoglin Structure and Function

DETERMINANTS OF ENDOGLIN PHOSPHORYLATION BY TRANSFORMING GROWTH FACTOR- RECEPTORS^*

Rositsa I. Koleva¹, Barbara A. Conley, Diana Romero, Kristin S. Riley, Jarrod A. Marto, Andreas Lux^¶, and Calvin P. H. Vary²

From the Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074, the Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, and the ^¶University Hospital Mannheim and Institute of Molecular Cell Biology, University of Applied Sciences, 68163 Mannheim, Germany

Determination of the functional relationship between the transforming growth factor- (TGF) receptor proteins endoglin and ALK1 is essential to the understanding of the human vascular disease, hereditary hemorrhagic telangiectasia. TGF1 caused recruitment of ALK1 into a complex with endoglin in human umbilical vein endothelial cells (HUVECs). Therefore, we examined TGF receptor-dependent phosphorylation of endoglin by the constitutively active forms of the TGF type I receptors ALK1, ALK5, and the TGF type II receptor, TRII. Of these receptors, TRII preferentially phosphorylated endoglin on cytosolic domain serine residues Ser⁶³⁴ and Ser⁶³⁵. Removal of the carboxyl-terminal tripeptide of endoglin, which comprises a putative PDZ-liganding motif, dramatically increased endoglin serine phosphorylation by all three receptors, suggesting that the PDZ-liganding motif is important for the regulation of endoglin phosphorylation. Constitutively active (ca)ALK1, but not caALK5, phosphorylated endoglin on cytosolic domain threonine residues. caALK1-mediated threonine phosphorylation required prior serine phosphorylation, suggesting a sequential mechanism of endoglin phosphorylation. Wild-type, but not a threonine phosphorylation-defective endoglin mutant blocked cell detachment and the antiproliferative effects of caALK1 expressed in HUVECs. These results suggest that ALK1 is a preferred TGF receptor kinase for endoglin threonine phosphorylation in HUVECs and indicate a role for endoglin phosphorylation in the regulation of endothelial cell adhesion and growth by ALK1.

Received for publication, February 9, 2006 , and in revised form, June 16, 2006.

^* This work was supported by Grant P20 15555 from the National Center for Research Resources, a component of the National Institutes of Health and by the Dana-Farber Cancer Institute (to J. A. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Dept. of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.

² To whom correspondence should be addressed: Center for Molecular Medicine, 81 Research Dr., Maine Medical Center Research Institute, Scarborough, ME 04074. Tel.: 207-885-8148; Fax: 207-885-8179; E-mail: varyc{at}mmc.org.

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