Bone morphogenetic protein signaling: implications in urology

Abstract

The bone morphogenetic proteins (BMPs), as members of the transforming growth factor-beta (TGF-beta) superfamily, not only control bone formation, but also regulate multiple key steps during embryonic development and differentiation. Furthermore, BMPs play critical roles in maintaining the homeostasis of the cardiovascular, pulmonary, reproductive, urogenital, and nervous systems in adult life. Like all members of the TGF-beta superfamily, BMP signaling is mediated through a heteromeric complex of type I and type II transmembrane serine/threonine kinase receptors. The subsequent signal transduction cascade includes either the canonical Smad-dependent or non-canonical Smad-independent pathways. Reflecting the critical function of BMPs, BMP signaling is tightly regulated at multiple steps by various mechanisms including extracellular endogenous antagonists, neutralizing antibodies/extracellular soluble receptor domains, small molecule inhibitors, cytoplasmic inhibitory Smads, and transcriptional co-repressors. Recently, dorsomorphin, the first small molecule inhibitor of BMP signaling, was identified and suggested as a useful tool for dissecting the mechanisms of signaling pathways and for developing novel therapeutics for diverse human diseases that are related to the BMP signaling pathways. In this article, we discuss various mechanisms involved in regulating BMP signaling pathways and their implications for urology.

Keywords: Bone morphogenetic proteins; Dorsomorphin; Signal transduction; Transforming growth factors.

FIG. 1

BMP signal transduction. BMP signaling is transduced by both type I and type II transmembrane serine/threonine kinase receptors. BMPs bind to the heteromeric complex of type I and type II receptors. Subsequently, type II receptor phosphorylates type I receptor, which in turn facilitates phosphorylation of R-Smads (Smad1, 5, and 8). R-Smads directly interact with activated type I receptor and are released upon phosphorylation. Following the release from the receptor complex, R-Smads complex with Co-Smad (Smad4) and translocate into the nucleus to modulate the transcription of target genes (canonical BMP-Smad pathway). Independent of the Smads, BMPs may transduce signal via the MAPK p38 pathway. Endogenous mechanisms of BMP signaling inhibition include extracellular antagonists such as noggin and chordin, inhibitory Smads (Smad6 and 7), Sno/Ski, and Smurfs. The small molecule inhibitor dorsomorphin inhibits type I BMP receptors. →: stimuation, ┆---: inhibition, BMPs: bone morphogenetic protein, BMPR: BMP receptor, pSmad: phosphorylated Smad, Smurf: Smad ubiquitination regulatory factor, XIAP: human X-chromosome-linked inhibitor of apoptosis protein, TAK1: TGFβ-activated kinase 1, NLK: Nemo-like kinase, JNK: Jun kinase, MAPK: mitogen-activated protein kinase.