HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE ADVANCED SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sammar, M. Articles by Knaus, P. Search for Related Content PubMed PubMed Citation Articles by Sammar, M. Articles by Knaus, P.

¹ Department of Physiological Chemistry, Biocenter, University of Würzburg, Germany
² Max-Planck-Institute for Molecular Genetics and Institute for Medical Genetics, Charité, Berlin, Germany
³ BIOPHARM GmbH, Heidelberg, Germany
⁴ Department of Genome Sciences, Graduate School of Medicine, Kobe University, Kobe, Japan
⁵ Institute for Biochemistry, FU Berlin, Thielallee 63, 14195 Berlin, Germany

The brachydactylies are a group of inherited disorders of the hands characterized by shortened digits. Mutations in the tyrosine kinase receptor Ror2 cause brachydactyly type B (BDB). Mutations in GDF5, a member of the BMP/TGF-ß ligand family, cause brachydactyly type C (BDC) whereas mutations in the receptor for GDF5, BRI-b, cause brachydactyly type A2 (BDA2). There is considerable degree of phenotypic overlap between the subtypes BDB, BDC and BDA2. Here we demonstrate that all three components are involved in GDF5 induced regulation of chondrogenesis. We show that Ror2 (tyrosine kinase receptor) and BRI-b (serine/threonine kinase receptor) form a ligand independent heteromeric complex. The frizzled-like-CRD domain of Ror2 is required for this complex. Within that complex Ror2 gets transphosphorylated by BRI-b. We show that Ror2 modulates GDF5 signalling by inhibition of Smad1/5 signalling and by activating a Smad-independent pathway. Both pathways however, are needed for chondrogenic differentiation as demonstrated in ATDC5 cells. The functional interaction of Ror2 with GDF5 and BRI-b was genetically confirmed by the presence of epistatic effects in crosses of Ror2, BRI-b and Gdf5 deficient mice. These results indicate for the first time a direct interaction of Ser/Thr- and Tyr-Kinase receptors and provide evidence for modulation of the Smad-pathway and GDF5 triggered chondrogenesis.

*Correspondence: E-mail: knaus{at}chemie.fu-berlin.de

This article has been cited by other articles:

				Y. Liu, J. F. Ross, P. V. N. Bodine, and J. Billiard Homodimerization of Ror2 Tyrosine Kinase Receptor Induces 14-3-3{beta} Phosphorylation and Promotes Osteoblast Differentiation and Bone Formation Mol. Endocrinol., December 1, 2007; 21(12): 3050 - 3061. [Abstract] [Full Text] [PDF]

				Y. Liu, R. A. Bhat, L. M. Seestaller-Wehr, S. Fukayama, A. Mangine, R. A. Moran, B. S. Komm, P. V. N. Bodine, and J. Billiard The Orphan Receptor Tyrosine Kinase Ror2 Promotes Osteoblast Differentiation and Enhances ex Vivo Bone Formation Mol. Endocrinol., February 1, 2007; 21(2): 376 - 387. [Abstract] [Full Text] [PDF]

				S. Mazerbourg, K. Sangkuhl, C.-W. Luo, S. Sudo, C. Klein, and A. J. W. Hsueh Identification of Receptors and Signaling Pathways for Orphan Bone Morphogenetic Protein/Growth Differentiation Factor Ligands Based on Genomic Analyses J. Biol. Chem., September 16, 2005; 280(37): 32122 - 32132. [Abstract] [Full Text] [PDF]

				A. Moustakas and C.-H. Heldin Non-Smad TGF-{beta} signals J. Cell Sci., August 15, 2005; 118(16): 3573 - 3584. [Abstract] [Full Text] [PDF]