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

Abstract

Bone morphogenetic proteins (BMPs) comprise the largest subfamily of TGF-␤-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. Bone morphogenetic proteins (BMPs) 1 are the largest subfamily of growth factors in the TGF-␤ superfamily and have been demonstrated to play important roles in endochondral bone formation and embryogenesis (1-4). Like other members of the TGF-␤ superfamily, BMPs appear to interact with type I and type II receptors on the cell surface (5). Following the expression cloning of the type II receptors for activin and TGF-␤ (6, 7), an increasing number of transmembrane serine/ threonine (Ser/Thr) kinases have been identified in mammals based on the conserved amino acid sequences in the intracellular kinase domain (8, 9). These include three distinct mammalian type I receptors for BMPs that are distinguished from the type I receptors for TGF-␤ (10 -12) and activin (11, 13) by the capability of binding ligand on their own when transfected into COS cells (5,14,15). BRK-1 (also known as ALK-3, TFR11, and BMPR-IA) binds BMP-2 and BMP-4 more efficiently than it binds BMP-7 (5, 14, 15). BRK-2 (also known as ALK-6, BMPR-IB, and RPK-1 (16)) binds both BMP-4 and BMP-7 efficiently (15). ActRI (also known as ALK-2 and SKR1) binds both activin and BMP-7 but does not bind BMP-4 (15, 17).The only type II receptors that have been identified for BMPs to date are from non-mammalian sources. The product of the daf-4 gene from Caenorhabditis elegans binds both BMP-2 and BMP-4 (18) and forms a complex with each of the BMP type I receptors in the presence of ligand (5, 15). The product of the punt gene from Drosophila, originally identified as the Drosophila homologue of the activin type II receptor (AtrII (19)), has recently been demonstrated to bind BMP-2 and is required for signaling by the Drosophila homologue of BMP-2 and BMP-4, the product of the decapentaplegic gene (20,21). The ability of the mammalian BMP type I receptors to form a complex with the nematode Daf-4 type II receptor as well as with other proteins having the expected size of the type II receptor in endogenous systems (5, 15) suggests the existence of mammalian BMP type II receptors. Indeed, expression of a BMP type I receptor in COS cells is insufficient to reproduce the high affinity binding observed in endogenous systems, suggesting that the high affinity complex is composed of both type I and type II receptor subunits (5). Since complex f...

A Kinase Domain-truncated Type I Receptor Blocks Bone Morphogenetic Protein-2-induced Signal Transduction in C2C12 Myoblasts

“…These results indicate that the truncated BMPR-IB does not bind BMP-2 with a high affinity in C2C12 cells. Interestingly, Nohno et al (27) reported that a truncated BMPR-II (BRK-3) did not efficiently cross-link to 125 I-BMP-4 when expressed alone in COS cells. However, coexpression of the truncated BMPR-II with the type I receptor enhanced the binding to 125 I-BMP-4.…”

“…2 This suggests that the BMP-2 signals are transduced by the complex of BMPR-IA and BMPR-II in these cells. It was reported that both BMPR-IA and BMPR-IB formed complexes with BMPR-II or DAF-4, a type II receptor for a homologue of BMP-2/BMP-4 in C. elegans, in a ligand-dependent manner when overexpressed together on the surface of COS cells (21,22,(25)(26)(27). In contrast to the truncated BMPR-IA, the kinase domain-truncated BMPR-IB did not inhibit the BMP-2 signaling in C2C12 cells even if its mRNA was abundantly expressed.…”

“…The structure of the type I receptor is conserved in all type I receptors of the TGF-␤ superfamily, suggesting that the BMP signals are transduced by the BMP type I receptor like those of TGF-␤. Two type I receptors (BMPR-IA and BMPR-IB) and one type II receptor (BMPR-II) have been identified for BMP-2 and BMP-4 (21)(22)(23)(24)(25)(26)(27). BMP-7 can interact with activin type I and type II receptors in addition to BMP-2/BMP-4 receptors (26,28).…”

The BMP signaling and in vivo bone formation

“…Three type I receptors have been shown to bind BMP ligands, type IA and IB BMP receptors (BMPR-IA or ALK-3 and BMPR-IB or ALK-6) and type IA activin receptor (ActR-IA or ALK-2) (Koenig et al, 1994;ten Dijke et al, 1994;Macias-Silva et al, 1998). Three type II receptors for BMPs have also been identified and they are type II BMP receptor (BMPR-II) and type II and IIB activin receptors (ActR-II and ActR-IIB) (Yamashita et al, 1995;Nohno et al, 1995;Rosenzweig et al, 1995;Kawabata et al, 1995). Whereas BMPR-IA, IB, and II are specific to BMPs, ActR-IA, II, and IIB are also signaling receptors for activins.…”

Bone Morphogenetic Protein (BMP) Type II Receptor Deletion Reveals BMP Ligand-specific Gain of Signaling in Pulmonary Artery Smooth Muscle Cells

“…Three type II receptors, BMPR2 and the activin type II receptors ActRIIa and ActRIIb (12)(13)(14)(15)(16)(17), can pair with three different type I receptors, ActRIa/ALK2, BMPRIa/ALK3, and BMPRIb/ALK6 (13, 18 -23), to transduce BMP signals. These various BMP receptors have distinct temporal and spatial expression in tissues and have varying affinities for each of more than 15 known BMP molecules (1,24).…”