IDENTIFICATION OF TYPE-I AND TYPE-II SERINE THREONINE KINASE RECEPTORS FOR GROWTH/DIFFERENTIATION FACTOR-5/

Growth/differentiation factor-5 (GDF-5) is a member of the bone morpho genetic protein (BMP) family, which plays an important role in bone de velopment in vivo. Mutations in the GDF-5 gene result in brachypodism in mice and Hunter-Thompson type chondrodysplasia in human. BMPs trans duce their effects through binding to two different types of serine/th reonine kinase receptors, type I and type II. However, binding abiliti es appear to be different among the members of the BMP family. BMP-4 b inds to two different type I receptors, BMP receptors type IA (BMPR-IA ) and type IB (BMPR-IB), and a type II receptor, BMP receptor type II (BMPR-II). In addition to these receptors, osteogenic protein-1 (OP-1, also known as BMP-7) binds to activin type I receptor (ActR-I) as wel l as activin type II receptors (ActR-II and ActR-IIB). Here we investi gate the binding and signaling properties of GDF-5 through type I and type II receptors. GDF-5 induced alkaline phosphatase activity in a ra t osteoprogenitor-like cell line, ROB-C26. I-125-GDF-5 bound to BMPR-I B and BMPR-II but not to BMPR-IA in ROB-C26 cells and other nontransfe cted cell lines. Analysis using COS-1 cells transfected with the recep tor cDNAs revealed that GDF-5 bound to BMPR-IB but not to the other ty pe I receptors when expressed alone. When COS-1 cells were transfected with type II receptor cDNAs, GDF-5 bound to ActR-II, ActR-IIB, and BM PR-II but not to transforming growth factor-beta type II receptor, In the presence of type II receptors, GDF-5 bound to different sets of ty pe I receptors, but the binding was most efficient to BMPR-IB compared with the other type I receptors. Moreover, a transcriptional activati on signal was efficiently transduced by BMPR-IB in the presence of BMP R-II or ActR-II after stimulation by GDF-5. These results suggest that BMPR-IB mediates certain signals for GDF-5 after forming the heterome ric complex with BMPR-II or ActR-II.