Identification of a Human Type II Receptor for Bone Morphogenetic Protein-4 That Forms Differential Heteromeric Complexes with Bone Morphogenetic Protein Type I Receptors

doi:10.1074/jbc.270.38.22522

Identification of a Human Type II Receptor for Bone Morphogenetic Protein-4 That Forms Differential Heteromeric Complexes with Bone Morphogenetic Protein Type I Receptors (*)

From the (1) Department of Pharmacology and
(2) Department of Biochemistry, Kawasaki Medical School, Kurashiki 701-01, Japan, the
(3) Department of Biological Science and Technology, Faculty of Engineering, University of Tokushima, Tokushima 770, Japan, and
(4) The Procter & Gamble Company, Corporate Research Division, Miami Valley Laboratories, Cincinnati, Ohio 45253-8707

^§ To whom all correspondence should be addressed. Tel.: 513-627-2550; Fax: 513-627-1612; rosenbaumjs{at}pg.com.

Abstract

Bone morphogenetic proteins (BMPs) comprise the largest subfamily of TGF-β-related ligands and are known to bind to type I and type II receptor serine/threonine kinases. Although several mammalian BMP type I receptors have been identified, the mammalian BMP type II receptors have remained elusive. We have isolated a cDNA encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type II receptor that binds BMP-4. This receptor (BRK-3) is distantly related to other known type II receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain. The BRK-3 gene is widely expressed in a variety of adult tissues. When expressed alone in COS cells, BRK-3 specifically binds BMP-4, but cross-linking of BMP-4 to BRK-3 is undetectable in the absence of either the BRK-1 or BRK-2 BMP type I receptors. Cotransfection of BRK-2 with BRK-3 greatly enhanced affinity labeling of BMP-4 to the type I receptor, in contrast to the affinity labeling pattern observed with the BRK-1 + BRK-3 heteromeric complex. Furthermore, a subpopulation of super-high affinity binding sites is formed in COS cells upon cotransfection only of BRK-2 + BRK-3, suggesting that the different heteromeric BMP receptor complexes have different signaling potential.

Footnotes

↵* This work was supported in part by grants-in-aids for scientific research from the Ministry of Education, Science and Culture of Japan and by a Research Project grant from Kawasaki Medical School (to T. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

BMP

bone morphogenetic protein

TGF-β

transforming growth factor-β

BRK

BMP receptor kinase

PCR

polymerase chain reaction

tBRK-3

truncated form of BRK-3

MISRII

Müllerian-inhibiting substance receptor type II.
↵²T. Nohno, T. Ishikawa, T. Saito, K. Hosokawa, S. Noji, J. Ting, B. B. Koenig, A. L. Pequet, and J. S. Rosenbaum, unpublished observations.
- Received June 7, 1995.
- Revision received July 7, 1995.