SMAD4  

SMAD4 属于 dwarfin/SMAD 家族。SMAD 是一组将细胞外信号直接传递至细胞核的蛋白质。哺乳动物细胞的 SMAD 可分为三类：受体调节 SMAD (R-SMAD)，共同介体 SMAD (Co-SMAD)，和抑制性 SMAD (I-SMAD)。(1) R-SMAD 包括 SMAD1、SMAD2、SMAD3、SMAD5 和 SMAD8/9，其中 SMAD2/3 主要介导 TGF-β 亚家族成员的信号传导，SMAD1/5/8 则介导来自骨形态发生蛋白 (BMP) 亚家族成员的信号传导。(2) Co-SMAD 包括 SMAD4，SMAD4 是 TGF-β 和 BMP 信号通路的中心介体。(3) I-SMAD 包括 SMAD6 和 SMAD7，能够抑制受体介导的 R-SMAD 磷酸化，从而防止与 Co SMAD形成复合物。SMAD4 对骨骼发育 (从软骨细胞前体到成熟骨细胞) 和组织稳态的细胞信号传导有重要作用。具体来说，TGF-β 在上游发出信号，激活 SMAD4 和 R-SMAD (即 SMAD2/3) 相互作用，形成调节靶基因表达的寡聚物复合物。而 SMAD3/4主要诱导人骨髓间充质干细胞的软骨生成。SMAD4 表达异常，会抑制动物模型中软骨产生，甚至引起细胞生长失控、诱导肿瘤。SMAD4 也特异性靶向干细胞，可能参与造血干细胞的自身更新。同时，SMAD4 调节软骨细胞的细胞极性，影响着软骨细胞形状、大小、迁移和定向。它还通过 SMAD4/TGF-β 通路促进不同细胞中的细胞迁移、粘附和细胞骨架组织生成。SMAD4/TGF-β 通路还会被经典途径广泛调节，如 MAPK、PI3K/AKT 和 WNT/β-catenin，以形成复杂的网络。SMAD4 还调节细胞凋亡，通过抑制颗粒细胞凋亡而导致卵泡闭锁。在结直肠癌癌症细胞中，TGF-β 诱导 SMAD4 依赖性的上皮-间充质转化，继而导致细胞凋亡。而 SMAD4 对细胞凋亡的保护作用也是其影响软骨细胞分化和增殖中的关键。并且，细胞凋亡对分化和骨稳态至关重要，即成骨细胞凋亡促进破骨细胞生成和骨吸收，这是骨稳态的重要过程。SMAD4 还控制早期肢芽中的基因调控网络，软骨细胞特异性 SMAD4-KO小鼠表现出侏儒症和生长板组织受损。SMAD4 蛋白还抑制上皮细胞增殖，并抑制减少血管生成、增加血管通透性，而显现出抗肿瘤作用^[1][2]。

SMAD4 belongs to the dwarfin/SMAD family. SMAD is a group of proteins that carry extracellular signals directly to the nucleus. Mammalian SMAD can be divided into three categories: receptor-regulated SMAD (R-SMAD), common-mediated SMAD (Co-SMAD), and inhibitory SMAD (I-SMAD). (1) R-SMAD included SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8/9, among which Smad2/3 mediated signal transduction of TGF-β subfamily members. SMAD1/5/8 mediates signaling from members of the bone morphogenetic proteins (BMP) subfamily. (2) Co-SMAD includes SMAD4, which is the central mediator of TGF-β and BMP signaling pathways. (3) I-SMAD, including SMAD6 and SMAD7, inhibits receptor-mediated phosphorylation of R-SMAD, thereby preventing the formation of complexes with Co SMAD. SMAD4 plays an important role in cellular signaling of bone development (from chondrocyte precursors to mature osteocytes) and tissue homeostasis. Specifically, TGF-β signals upstream to activate SMAD4 and R-SMAD (i.e. SMAD2/3) to interact and form oligomer complexes that regulate the expression of target genes. However, SMAD3/4 mainly induced chondrogenesis of human bone marrow mesenchymal stem cells. Abnormal expression of SMAD4 can inhibit cartilage production in animal models, and even lead to uncontrolled cell growth and tumor induction. SMAD4 also specifically targets stem cells and may be involved in self-renewal of hematopoietic stem cells. At the same time, SMAD4 regulates the cell polarity of chondrocytes, affecting the shape, size, migration and orientation of chondrocytes. It also promotes cell migration, adhesion and cytoskeletal tissue generation in different cells through the SMAD4/TGF-β pathway. The SMAD4/TGF-β pathway is also extensively regulated by classical pathways such as MAPK, PI3K/AKT, and WNT/β-catenin to form complex networks. SMAD4 also regulates apoptosis, leading to follicular atresia by inhibiting granulosa cell apoptosis. In colorectal cancer cells, TGF-β induces Smad4-dependent epithelial-mesenchymal transformation, which leads to apoptosis. The protective effect of SMAD4 on apoptosis is also the key to the differentiation and proliferation of chondrocytes. In addition, apoptosis is crucial for differentiation and bone homeostasis, that is, osteoblast apoptosis promotes osteoclast generation and bone resorption, which is an important process of bone homeostasis. SMAD4 also controls gene regulatory networks in early limb buds, and chondrocyte specific Smad4-KO mice exhibit dwarfism and impaired growth plate tissue. SMAD4 protein also inhibited epithelial cell proliferation and decreased angiogenesis and increased vascular permeability, showing antitumor effects^[1][2].

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