Survey Recent advances in BMP receptor signaling Christina Sieber, Jessica Kopf, Christian Hiepen, Petra Knaus * Institute for Chemistry and Biochemistry, Freie Universita ¨t Berlin, Thielallee 63, 14195 Berlin, Germany Contents 1. Introduction ..................................................................................................... 344 2. Role of BMPs during early vertebrate development ...................................................................... 344 3. Main players in BMP signaling ...................................................................................... 345 3.1. Ligands ................................................................................................... 345 3.2. Receptors .................................................................................................. 345 3.3. Ligand–receptor oligomerization and signaling.................................................................... 345 4. Regulation and finetuning of BMP signaling............................................................................ 346 4.1. Antagonists ................................................................................................ 346 4.2. Co-receptors ............................................................................................... 346 4.3. Intracellular regulatory proteins ............................................................................... 346 5. Downstream signaling ............................................................................................. 348 5.1. Smad signaling ............................................................................................. 348 5.2. Regulation of the Smad pathway and its crosstalks ................................................................ 348 5.3. The role of endocytosis in BMP signaling ........................................................................ 349 5.4. BMPs and mechanotransduction ............................................................................... 349 5.5. Non-Smad signaling ......................................................................................... 349 5.6. Non-transcriptional effects of BMP signaling ..................................................................... 350 6. BMP signaling under physiological conditions .......................................................................... 350 6.1. BMPs in cell polarity and migration ............................................................................ 350 6.2. BMPs in quiescence and angiogenesis ........................................................................... 351 Cytokine & Growth Factor Reviews 20 (2009) 343–355 ARTICLE INFO Article history: Available online 7 November 2009 Keywords: BMP Migration Cytoskeletal rearrangements Smad PAH ABSTRACT Bone Morphogenetic Proteins (BMPs) play an important role during organ development and during regeneration after tissue damage. BMPs signal via transmembrane serine/threonine kinase receptors. From our current understanding heteromeric complexes of type I and type II receptors are required for signal propagation. Presently, three type I and three type II receptors are known to bind BMPs with different affinities. Ligands and receptors eventually oligomerize via defined modes into signaling complexes. Co-receptors recruit into these complexes to either inhibit or to promote signaling. The Smad pathway, initiated by phosphorylation through the activated type I receptors, results in transcriptional regulation of early target genes. However, on its way to the nucleus, Smads represent signaling platforms for other pathways, which eventually finetune BMP signal transduction. We also describe BMP-induced signaling cascades leading to cytoskeletal rearrangements, non-transcriptional and non-Smad path- ways. BMPs induce a plethora of different cellular effects ranging from stem cell maintenance, migration, differentiation, proliferation to apoptosis. The molecular mechanism, by which the same ligand induces these manifold effects, depends on the cellular context. Here we try to give a current picture of the most important players in regulating and directing BMP signaling towards the desired cellular outcome. Examples of BMP action during development, but also physiological and pathophysiological conditions in the adult organism are presented. ß 2009 Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: +49 30 838 52935; fax: +49 30 838 51935. E-mail address: knaus@chemie.fu-berlin.de (P. Knaus). Contents lists available at ScienceDirect Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr 1359-6101/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.cytogfr.2009.10.007