BMP signaling pathway

The fate of neural precursors in the developing brain is determined by intrinsic cellular programs and by external cues mediated by cytokines. Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily, are active in many tissues under normal physiologic conditions, and are regulated through reversible interactions with extracellular antagonists, including noggin, chordin, follistatin, and DAN. The interaction of BMPs with extracellular antagonists determine the bioavailability of BMPs for binding to their cognate receptors and activation of down-stream responses. BMPs are classified into several subgroups on the basis of sequence similarities and homology. Apart from their ability to induce ectopic bone formation, cartilage condensation, chondrocyte maturation, and interdigital cell death, BMPs are involved in many developmental processes, including cell proliferation, differentiation, and apoptosis. The action of BMPs is mediated by BMPRI and BMPRII. BMPRI phosphorylates specific molecules in the cytoplasm, resulting in increased alkaline phosphatase activity, proteoglycan synthesis, and collagen synthesis. Two specific forms of BMPRI include Type IA and Type IB which dimerize with BMPRII in the presence of BMP2, BMP4 and BMP7. Binding of BMPs to the BMPR complex results in the activation of BMPRI, which in turn phosphorylates SMAD1, SMAD5 and SMAD8 molecules. Upon phosphorylation, these BMP-specific SMADs form a complex with the co-SMAD SMAD4 and translocate into the nucleus to activate transcription of specific genes. In the nucleus, the SMAD1-SMAD4 complex binds with low affinity to the GCCG or CAGA motif in the promoter regions of many BMP-responsive genes. They are also recruited to the promoters of BMP-responsive genes by high affinity cofactors such as OAZ, which binds to the promoter of the Xvent2 gene.SMAD1 forms a complex with p300/CBP, FAST1, FAST2, and STAT3, and this complex is involved in the transactivation of the glial fibrillary acidic protein gene. In addition, SMAD1 interacts with SIP1, the acute myelogenous leukemia protein, and the homeodomain transcription factor Hoxc8. Inhibitory SMAD proteins, SMAD6 and SMAD7, repress the action of BMP by inhibiting the receptor-mediated phosphorylation of SMAD1, SMAD5, or SMAD8 or by competing with SMAD4 for the binding to SMAD1, SMAD5 and SMAD8. In the ectoderm, BMPs activate two biochemical pathways, one mediated by SMADs and a second mediated by the p38 MAPK pathway downstream of TAK1. TAB1/2 are key effectors in the activation of the NF-κB and JNK pathways. When BMP, PKA and CalmK IV pathways are activated simultaneously, CREB becomes phosphorylated, binds to CBP, and disrupts interactions between limiting amounts of CBP and the hematopoietic-specific DNA binding proteins. BMPs initiate the recruitment of progenitor and stem cells towards the area of bone injury, stimulate both angiogenesis and the proliferation of stem cells from surrounding mesenchymal tissues, and promote maturation of stem cells into chondrocytes, osteoblasts, and osteocytes. BMPs are also involved in the regulation of other biological processes unrelated to bone formation. They play essential role in early vertebrate embryogenesis such as in mesoderm induction, limb development, stimulation of proteoglycan synthesis, alkaline phosphatase activity, collagen synthesis, osteocalcin expression in chondroblasts/osteoblasts, and hematopoietic formation.