Bone morphogenetic protein receptors: Structure, function and targeting by selective small molecule kinase inhibitors

Bone, vol. 138, pp. 115472

Abstract

Bone morphogenetic proteins (BMPs) are secreted cytokines that control the fate and function of many different cell types. They exert their cellular responses via heteromeric complexes of specific BMP type I and type II serine/threonine kinase receptors, e.g. BMPRIA and BMPRII. Three type II and four type I receptors, also termed activin receptor-like kinases (ALKs), have been identified. The constitutively active type II kinase phosphorylates the type I receptor, which upon activation initiates intracellular signaling by phosphorylating SMAD effectors. Auxiliary cell surface receptors without intrinsic enzymatic motifs, such as Endoglin and Repulsive guidance molecules (RGM), can fine-tune signaling by regulating the interaction of the BMP ligands with the BMPRs. The functional annotation of the BMPR encoding genes has helped to understand underlying mechanisms of diseases in which these genes are mutated. Loss of function mutations in BMPRII, Endoglin or RGMc are causally linked to pulmonary arterial hypertension, hereditary hemorrhagic telangiectasia and juvenile hemochromatosis, respectively. In contrast, gain of function mutations in ACVR1, encoding ALK2, are linked to Fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. Here, we discuss BMPR identification, structure and function in health and disease. Moreover, we highlight the therapeutic promise of small chemical compounds that act as selective BMPR kinase inhibitors to normalize overactive BMPR signaling.

Authors 5

1. Gonzalo Sánchez‐Duffhues corresponding Aachen Department of Cell and Chemical Biology

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands. Electronic address: g.sanchez_duffhues@lumc.nl

   Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands

2. Eleanor Williams

   University of Oxford

   Affiliation as printed

   Structural Genomics Consortium, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK

3. Marie‐José Goumans Aachen Department of Cell and Chemical Biology

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands

4. Carl‐Henrik Heldin

   Uppsala University · Science for Life Laboratory

   Affiliation as printed

   Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden

5. Peter ten Dijke corresponding Aachen Department of Cell and Chemical Biology Oncode Institute

   Leiden University · Uppsala University · Leiden University Medical Center · Science for Life Laboratory · Oncode Institute

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden; Oncode Institute, Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands. Electronic address: p.ten_dijke@lumc.nl

   Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands

   Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden

   Oncode Institute, Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands