Bone morphogenetic protein receptor signal transduction in human disease

作者：Maria Catalina Gomez‐Puerto, Prasanna Vasudevan Iyengar, Amaya García de Vinuesa, Peter ten Dijke, Gonzalo Sánchez‐Duffhues · 发表于：The Journal of Pathology · 年份：2018 · DOI：10.1002/path.5170 · 被引用次数：240 · 研究领域：TGF-β signaling in diseases、Heterotopic Ossification and Related Conditions、Bone Metabolism and Diseases

Bone morphogenetic proteins (BMPs) are secreted cytokines that were initially discovered on the basis of their ability to induce bone. Several decades of research have now established that these proteins function in a large variety of physiopathological processes. There are about 15 BMP family members, which signal via three transmembrane type II receptors and four transmembrane type I receptors. Mechanistically, BMP binding leads to phosphorylation of the type I receptor by the type II receptor. This activated heteromeric complex triggers intracellular signaling that is initiated by phosphorylation of receptor-regulated SMAD1, 5, and 8 (also termed R-SMADs). Activated R-SMADs form heteromeric complexes with SMAD4, which engage in specific transcriptional responses. There is convergence along the signaling pathway and, besides the canonical SMAD pathway, BMP-receptor activation can also induce non-SMAD signaling. Each step in the pathway is fine-tuned by positive and negative regulation and crosstalk with other signaling pathways. For example, ligand bioavailability for the receptor can be regulated by ligand-binding proteins that sequester the ligand from interacting with receptors. Accessory co-receptors, also known as BMP type III receptors, lack intrinsic enzymatic activity but enhance BMP signaling by presenting ligands to receptors. In this review, we discuss the role of BMP receptor signaling and how corruption of this pathway contributes to cardiovascular and musculos...