SMAD5  

SMAD5 是一种受体激活的 Smad (R-Smad)，也称为 dwarfin C, JV5-1 和 MAD5，属于 dwarfin/SMAD 家族。SMAD5 蛋白由负责 DNA 结合的 N端结构域、主要用于蛋白质-蛋白质相互作用的 C 端结构域和包含泛素化降解所必需的基序的连接区组成。SMAD5 被活化的 I 型 TGF-β 受体激活，磷酸化的 SMAD5 再与 SMAD4 (通用 SMAD) 结合，形成异三聚体复合物，作为转录因子进入细胞核。同时，SMAD4 也会被抑制性 SMAD (SMAD6 和 SMAD7) 结合，使 R-Smad 竞争受体或与 Smad4 的相互作用，并靶向降解、负调节 TGF-β 信号传导。SMAD5 主要响应 BMP 信号通路。在胚胎发育过程中，小鼠 SMAD5 从原肠形成开始广泛表达。期间，SMAD5 的缺失会导致胚胎突变，或胚胎外卵黄囊缺陷，并在妊娠中期死亡。而且，BMP/SMAD5 通路可以调控成骨过程，通过上调转录因子 Runx2 的转录，或靶向成骨特异性基因中的多个顺式作用启动子元件，包括骨钙素和碱性磷酸酶 (ALP)。ALP 能够结合 Smad 相互作用蛋白 1 (SIP1)，抑制 SMAD5 诱导的 SIP1 激活。据报道，SMAD5 缺陷小鼠的胚胎干细胞中，表现出正常末端成熟的原始多潜能祖细胞的显著扩增，说明了 SMAD5 特异性信号通路的条件激活或失活可能有助于造血和成骨组织工程^[1]。

SMAD5 is a receptor activated Smad (R-Smad), also known as dwarfin C, JV5-1 and MAD5, which belong to the dwarfin/SMAD family. The SMAD5 protein consists of an N-terminal domain responsible for DNA binding, a C-terminal domain primarily used for protein-protein interactions, and a junction region containing moths necessary for ubiquitination degradation. SMAD5 is activated by an activated type I TGF-β receptor, and phosphorylated SMAD5 binds to SMAD4 (common SMAD) to form heterotrimer complexes that enter the nucleus as transcription factors. At the same time, SMAD4 is also bound by inhibitory SMAD (SMAD6 and SMAD7), making R-Smad compete for receptors or interact with Smad4, and target degradation and negative regulation of TGF-β signaling. SMAD5 mainly responds to BMP signaling pathways. During embryonic development, SMAD5 is widely expressed in mice from gastrum formation. During this period, the loss of SMAD5 leads to mutations in the embryo, or defects in the yolk sac outside the embryo, and death in the second trimester. Furthermore, the BMP/SMAD5 pathway can regulate osteogenesis by up-regulating transcription of the transcription factor Runx2, or by targeting multiple cis-acting promoter elements in osteogenic specific genes, including osteocalcin and alkaline phosphatase (ALP). Alps bind to Smad interacting protein 1 (SIP1) and inhibit Smad5-induced SIP1 activation. A significant expansion of primitive multipotent progenitor cells showing normal terminal maturation was reported in embryonic stem cells from Smad5-deficient mice, suggesting that conditional activation or deactivation of Smad5-specific signaling pathways may contribute to hematopoietic and osteogenic tissue engineering^[1].

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