Figure 4

Schematic representation of BMP signaling and its regulation. (a) The basic helix-loop-helix (bHLH) proteins and its binding sequence (E-box) regulate the tissue-specific expression of the BMP gene. Osteogenic lineage-specific novel transcriptional factors can recognize the E-box. (b) Noncanonical Smad-independent signaling pathway. p38 activated MAPK pathway could converge at the Runx2 gene to control MPCs differentiation and TAK1 (TGF-β-activated kinase 1) signaling may also regulate bone formation. TGF-β-induced receptor heterotetramer recruit the ubiquitin ligase tumor necrosis factor α receptor associated factor 6 (TRAF6) to cytoplasmic domain. TRAF6 ubiquitylates and activates the catalytic activity of TAK1 and MAP3K7, leading to activation of the p38 and c-Jun N-terminal kinase (JNK) cascades, which regulate apoptosis and cell migration. The TGF-β type I receptor phosphorylates both serine and tyrosine residues in the SHCA (SHC1) adaptor, which then recruits the adaptor protein GRB2 and the Ras guanine exchange factor (GEF) son of seven less (SOS) in mammalian cells. This leads to activation of the Ras-Raf-MEK-Erk, MAPK JNK-c-Jun N terminal kinase, ATF-2 (activating transcription factor-2); p38 (p38 MAPK), SHCA (SH2 domain-containing sequence A), and Erk (extracellular signal regulated kinase). (c) Smad dependent pathway or the canonical BMP molecular signaling pathway. Type II BMP receptor and type I BMP receptor is housed in a specific membrane domain of CAV1β and clathrin-coated pits at cell surface. RGM acts as co-receptor of BMP signaling. Meanwhile BMP ligand dimer binds to BMPRII, BMPRI is cross-phosphorylated at GS site, and recruits R-Smad to the intracellular domain of the BMPR-I and initiates signal transduction via phosphorylation. Activated R-Smad then forms a heteromeric complex with C-Smad. This complex is translocated into the nucleus and interacts with several transcription factors such as Runx2/Cbfα1 (core binding factor alpha 1), Osx (Osterix), Dlx5, and Msx2 (msh homeobox homolog 2). These molecules mediate the transcription of related genes to induce osteogenesis. However, Smad complex binds the Id1 promoter that contains two critical motifs, i.e., SBEs and Bre7 motif. Noggin, twisted gastrulation (Tsg), and other antagonists bind to BMP ligands and block signaling. I-Smads reside in the nucleus, migrate to the cytoplasm and can negatively regulate BMP signaling by inhibiting signal transduction at several points. (d) Smad complex regulation inside the nucleus. The activated Smad complex interacts with a choice of Smad partners (transcription factors for instance BRG1 (Brahma-related gene 1), ETS1 (v-ets erythroblastosis virus E26 oncogene homolog 1), HHM (human homolog of Maid), IKKα (IκB kinase α), Smurf2, TFAP2A (transcription factor activating enhancer-binding protein 2α) and undergoes post-translational modifications. When the SNON/SKI are proteasomally degraded after being ubiquitylated by the ubiquitin ligases arkadia, Smurf2 or APC (anaphase-promoting complex)/CDH1 (ubiquitin ligase subunit) and thereby Smad target genes are inhibited. Nuclear R-Smads (e.g., Smad3) target the co-repressor SnoN for degradation via Smurfs or the APC that act as E3 ligases.⁹