SMAD4是抑癌基因，编码蛋白是一种转录因子，在转化生长因子β（TGF-β）信号通路中起着关键作用。TGF-β信号转导控制多种生物学过程，包括细胞增殖、分化和组织稳态。SMAD信号分子在细胞因子TGF-β超家族（如TGFβ1、TGFβ2、TGFβ3、激活素和淋巴结）的结合下被膜受体丝氨酸激酶激活。TGFβ依赖性的转录的背景属性允许TGF-β途径抑制癌前状态的肿瘤发生，并促进癌症进展过程中的侵袭和转移。SMAD4的胚系突变与幼年息肉病综合征（JPS）有关。SMAD4表达缺失或体细胞突变常发现于胰腺癌，并与肿瘤分级有关。SMDA4的体细胞改变在包含结肠和肺腺癌的多个肿瘤类型中以较低频率出现。

SMAD4 is a transcription factor that functions as a critical effector in the transforming growth factor beta (TGFß) signal pathway. TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis. The SMAD receptor-regulated signaling molecules (such as SMAD2 and SMAD3) are activated by membrane receptor serine kinases following binding of TGFß superfamily of cytokines (e.g. TGFß1, TGFß2, TGFß3, activin and nodal). Following dimerization and activation of TGFß receptors, two phosphorylated receptor-regulated SMAD proteins form a trimeric complex with SMAD4 to allow for binding to DNA. The SMAD trimeric complex can translocate to the nucleus and regulate TGFß-mediated gene transcription in a cell-type dependent manner specified, in part, by the availability of transcriptional co-activators and chromatin accessibility. The contextual nature of TGFß-dependent transcription allows the TGFß pathway to suppress tumorigenesis in premalignant states and promote invasiveness and metastasis during cancer progression . Germline mutations in SMAD4 have been associated with juvenile polyposis syndrome (JPS). Loss of SMAD4 expression or somatic mutations in SMAD4 are found in pancreatic cancer and are associated with tumor grade. Somatic alterations in SMAD4 are observed at lower frequencies in multiple tumor types, including colon and lung adenocarcinoma.

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