TOB in Osteoblast Signaling
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TOB in Osteoblast Signaling
TOB (Transducer of ErbB2), a member of the TOB and BTG (B-cell Translocation Gene) anti-proliferative protein family, negatively regulates the proliferation of Osteoblasts (Ref.1). Bone is formed and resorbed continuously, starting in the embryo and continuing throughout adult life. This process occurring in adult bone is called bone remodeling. Bone remodeling is accomplished by precise coordination of two cell types, Osteoblasts and Osteoclasts (Ref.2). Osteoblasts deposit calcified bone matrix, and Osteoclasts resorb it. Deregulation of bone remodeling leads to metabolic bone disease. Osteoporosis, for example, is characterized by reduced bone mass and it results from an imbalance between bone formation and resorption. Therefore, bone remodeling needs a proper regulatory mechanism. Bone formation, a direct outcome of Osteoblast proliferation and differentiation, needs timely regulation for requisite bone formation. BMPs (Bone Morphogenetic Proteins) control Osteoblast proliferation (Bone Formation) through SMAD proteins. TOB, as a SMAD-inhibitor, plays a critical role in BMP2-SMAD -regulated gene expression in Osteoblasts (Ref.3).

BMP2 signals through heteromeric complexes of transmembrane Serine/Threonine kinase receptors: BMPRI (BMP Receptor Type-I) and BMPRII, which then propagate signals to the SMAD pathway. Binding of BMP2 to its receptor complex results in the phosphorylation of R-SMADs (Receptor-Regulated SMADs): SMAD1, SMAD5 and SMAD8 molecules. R-SMADs are phosphorylated by the BMPRI on the carboxy-terminal SSXS motif. Once phosphorylated, R-SMADs dissociate from the receptor, form a complex with the Co-SMAD, SMAD4, and enter the nucleus to activate transcription of specific genes like, p300, CBP (CREB- Binding Protein), CREB (cAMP Response Element-Binding Protein) etc., involved in Osteoblast proliferation and differentiation. The TOB gene is also induced in response to BMP2 (Ref.4). Consequently, TOB accumulates in the nucleus and recruits R-SMADs to nuclear bodies by binding to the MH2 domain of the phosphorylated R-SMADs. Overproduction of TOB represses the BMP2-induced, SMAD-mediated transcriptional activation. TOB colocalizes with R-SMADs as well as SMAD4 in nucleus upon BMP2 stimulation. The abilities of R-SMADs to heterooligomerize with SMAD4 are not affected by coexpression of TOB, suggesting that the TOB-SMAD complex consists of the R-SMADs, SMAD4, and TOB protein. This initiates a negative feedback mechanism, allowing a precise and timely regulation of BMP2 signaling and proper bone formation (Ref.2).