512 white adipose tissue, is essential in energy expenditure and may be a potential treatment for obesity [17]. 　Consistent with the diverse function of BMPs, BMP sig- naling is mediated through complex signal transduction pathways. Currently, over 20 known BMP ligands exert their effects through a heteromeric complex of both type I and type II transmembrane serine/threonine kinase re- ceptors [18]. Following binding of the ligands, the combina- tion of type I and type II receptors initiates a subsequent signal transduction cascade by phosphorylating Smads, which in turn rapidly move into the nucleus to modulate transcription [19]. Alternatively, BMP signaling involves Smad-independent pathways that include mitogen-acti- vated protein kinase (MAPK) p38 [20]. Due to the critical role of BMPs, BMP signaling is tightly regulated at multi- ple steps throughout its signal transduction cascade. Among these regulatory mechanisms are endogenous in- hibitors of BMPs such as noggin, which inhibit BMPs by sequestering the ligands [21,22]. In contrast, a small mole- cule inhibitor of BMPs, dorsomorphin, acts as a specific in- hibitor of the BMP receptor type I. Because of this specific- ity, dorsomorphin may be a useful tool for dissecting the mechanisms of BMP signaling pathways in many bio- logical processes as well as for developing novel therapeu- Jeong et al tics for various human diseases [23]. 　In this review, we summarize the current understanding of BMP signaling pathways and their regulatory mecha- nisms in depth, with a particular focus on the negative reg- ulators, including endogenous and small molecule inhi- bitors. COMPLEXITY OF BMP SIGNALING The basic mechanism of BMP signaling has been well char- acterized by many investigators (Fig. 1). BMP signaling is transduced by a heteromeric complex of type I and type II transmembrane serine/threonine kinase receptors [18]. To date, three distinct type I receptors, activin receptor-like kinase 2 (ALK2), BMP type IA receptor (BMPR-IA/ALK3), and BMP type IB receptor (BMPR-IB/ALK6), have been identified [24]. Likewise, three type II receptors consisting of BMP type II receptor (BMPR-II), activin type IIA re- ceptor (ActR-IIA), and activin type IIB receptor (ActR-IIB) have been described [25]. Both type I and type II receptors serve as components for the heteromeric, likely hetero- tetrameric, receptor complexes to which BMP ligands bind. Initially, the ligand binds to type II receptor, which then recruits type I receptor. Subsequently, type II receptor 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. Korean J Urol 2010;51:511-517