513 TABLE 1. Summary of the inhibitory mechanisms of BMP signal- ing Classification Name Roles Endogenous antagonists Noggin Induce neural tissue, Limb development BMP-2,-4: high affinity, BMP-7: low affinity Chordin Induce neural tissue, Limb development Cerberus Formation of head structure Caronte Development of left-right symmetry Follistatin, Gremlin Limb development Neutralizing antibody/soluble receptors Myostatin High affinity anti-BMP antibody Small molecule inhibitors Dorsomorphin BMPs and Urology phosphorylates type I receptor, which in turn facilitates a subsequent signal transduction cascade by phosphorylat- ing Smads, a group of intracellular mediators of BMP sig- naling [19]. 　Smads involved in BMP signaling are divided into three functional groups: 1) receptor-regulated Smads (R-Smads/ Smad1, 5, and 8), 2) common-partner Smad (Co-Smad/ Smad4), and 3) inhibitory Smads (I-Smads/Smad6 and 7) [19]. R-Smads directly interact with activated type I re- ceptor and are phosphorylated. Activated R-Smads then form complexes with the lone Co-Smad. These R-Smads/ Co-Smad complexes translocate into the nucleus to modu- late the transcription of target genes [26]. In this Smad-de- pendent process, type I receptors appear to be key modu- lators of the specificity of BMP signaling pathways. For ex- ample, BMP-6 has a higher affinity for ALK2 receptor, through which Smad 1 and 5 are preferentially phosphory- lated and activated. On the other hand, BMP-7 binds to all three type I receptors (ALK2, ALK3, and ALK 6), showing different patterns of affinity, and therefore all the R-Smads (Smad1, 5, and 8) are likely involved [15]. 　Although BMPs activate Smads for their signaling and it is clear that Smads are critical for BMP signaling path- ways to modulate target gene transcription, alternative pathways different from the Smad pathway have been suggested. Like TGF-β and activin, BMP signaling can ac- tivate the mitogen-activated protein kinase (MAPK) p38 pathway independent of the Smads [20]. It has been pro- posed that ligand binding between BMPs and preformed heterodimeric receptor complexes leads to the Smad-de- pendent pathway, whereas induction of receptor com- plexes by the ligand results in the activation of the alter- native MAPK p38 pathway [27,28]. REGULATION OF BMP SIGNALING Reflecting the critical roles of BMPs, BMP signaling is tightly regulated at multiple levels throughout its signal- ing cascades. Extracellular endogenous antagonists com- pose the first level of regulation, followed by cytoplasmic inhibitory Smads and transcriptional co-repressors (Table 1). 1. Endogenous antagonists of BMPs Various endogenous antagonists of BMPs, such as noggin, chordin, follistatin, gremlin, ectodin, cerberus, caronte, and sclerostin, are secreted into the extracellular space [29]. These secreted antagonists directly bind to BMP li- gands, sequester active BMPs extracellularly, and prevent the binding of BMPs to the receptors [30]. The biological effects of these endogenous antagonists vary as they re- strict and terminate BMP signaling. 　Tight regulation of BMP signaling through the endoge- nous inhibitors is crucial during early embryogenesis [31]. Noggin and chordin induce neural tissue from ectoderm and dorsalize ventral mesoderm [32], whereas cerberus plays a critical role in the formation of the head [33]. Inhibitor of type I receptors ALK-2,-3,-6 Blocking phosphorylation of Smad 1/5/8 Antagonist of R-Smad and Co-Smad signaling Blocking the process of complex formation (R-Smad/Co-Smad) Induce degradation of R-Smads by ubiquitination Cytoplasmic inhibitory Smads I-Smad (-6, -7) Ski/SnoN Smurf BMP: bone morphogenetic protein, ALK: activin receptor-like kinase, Smurf: Smad ubiquitination regulatory factor Similarly, caronte regulates left-right symmetry [34], whereas limb development is controlled by noggin, chor- din, follistatin, and gremlin [35-39]. The varying effects of these endogenous BMP antagonists are likely mediated by the differing affinity for BMP subtypes. For example, nog- gin has high affinity for BMP-2 and BMP-4 but low affinity for BMP-7; noggin also competes against gremlin and cer- berus for BMP-2 [40,41]. 　The precise regulation of expression of these endogenous BMP antagonists remains to be elucidated. Nevertheless, a negative feedback look appears to be one important mechanism. For example, the increased expression of BMP-6 in prostate cancer cells has been associated with elevated levels of expression of noggin [42]. Similarly, in osteoprogenitor cells, expression of noggin is induced by BMP-2, 4, and 6 and the resulting increase in noggin de- creases the bioactivity of these BMPs in a negative feed- back loop [43]. 2. Cytoplasmic inhibitors of Smads Within the cytoplasm, the bioactivity of R-Smads (Smad1, 5, and 8) and Co-Smad (Smad4) is regulated by various inhibitors. These cytoplasmic antagonists of BMP signal- Korean J Urol 2010;51:511-517