Target Name: SMAD4
NCBI ID: G4089
Other Name(s): Smad
Drug Target Analysis Report Drug Target Analysis Report Content

About the Target

SMAD4, a protein involved in signaling pathways of the TGF-beta superfamily, plays a crucial role as the common mediator for TGF-beta and bone morphogenic protein (BMP) signaling [1]. It consists of three main domains: the N-terminal MH1 domain, the C-terminal MH2 domain, and the linker region between them [1]. Additionally, there are other SMAD proteins that have specific functions, such as SMAD2/3 that mediate signaling from TGF-beta subfamily members and SMAD1/5/8 that transduce signaling from BMP subfamily members [1].

In pathological conditions like thoracic aortic aneurysm and dissection (TAAD), a variant in the SMAD4 gene (rs12455792 C>T) is suggested to suppress SMAD4 expression, leading to the activation of TGF-beta signaling, chemotactic factors production, and subsequent recruitment of monocytes and vessel remodeling, contributing to the progression of TAAD [2].

NRF1, a transcription factor, has a role in modulating TGF-beta and SMAD4-mediated signal transduction pathways affecting the survival of cancer cells [3]. It is proposed that NRF1 may interact with SMAD4 to regulate the transcription of the p15INK4b gene, although the exact mechanism remains unknown [3].

SMAD4 deficiency in pancreatic ductal adenocarcinoma (PDAC) cells results in the over-activation of the downstream oncogene HNF4G, which promotes tumor invasion and metastasis [4]. In contrast, in PDAC cells where SMAD4 is present, the expression of HNF4G is physiologically inhibited by the SMAD complex [4]. Metformin, a drug, is suggested to repress PDAC invasion and metastasis by activating AMPK, which leads to the degradation of HNF4G [4].

In developing neural progenitor cells (NPCs), BMPs (bone morphogenic proteins) play a role in fate determination. When NPCs progress, repressive epigenetic marks are removed, allowing for neurogenic genes to be expressed [5]. Upon BMP stimulation, activated Smads, including SMAD4, bind to reachable consensus sequences, and stage-specific Smad partners regulate the induction of fate-specific genes [5].

In summary, SMAD4 plays a critical role in TGF-beta and BMP signaling pathways, and its dysregulation can have implications in various pathological conditions and cancer progression. The interaction between SMAD4 and other proteins or transcription factors contributes to the regulation of gene expression and cell fate determination.
Based on the provided context information, here are some key viewpoints regarding SMAD4:

In advanced colon cancer, both activin and TGFbeta signaling pathways utilize SMAD4 to regulate the upregulation of p21, a protein involved in growth suppression [6].
However, in colon cancer, there is ligand-specific SMAD4-independent signaling that utilizes distinct mitogenic signaling pathways [6].
Activin signaling in colon cancer dominantly induces downregulation of p21 through the PI3K/Akt signaling pathway, which is different from the early SMAD4-dependent upregulation of p21 [6].
The expression of nuclear p21 in colon cancer may serve as a functional surrogate for intact TGFbeta/SMAD growth suppression and also as a negative predictor for growth-enhancing response to TGFbeta pathway inhibition [6].
In contrast, colon cancers with loss of nuclear p21 may benefit from activin, TGFbeta, or combination inhibitory therapy [6].
Feedback loops and complex parallel signaling pathways operate downstream of activin and TGFbeta in colon cancer, and understanding their interplay is crucial for predicting the effects of targeted pathway disruption on tumor behavior [6].

In the context of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, the mutation of SMAD4 is one of the key genetic alterations that occurs during the progression from low-grade lesions to invasive phenotypes [7].
Mutations in TP53 and SMAD4 are associated with malignant transformation in mucinous cystic adenomas of the pancreas [7].
Loss of p16 expression increases as IPMNs progress from non-invasive to invasive disease [7].

10. USP7-mediated autoregulation of SMAD3 involves the monoubiquitination of SMAD3, which inhibits its interaction with coregulatory SMAD4 and impairs their DNA-binding function. USP7 acts as a deubiquitinase for SMAD3, removing mono-ubiquitin and allowing it to form a heterodimer with SMAD4 to enhance the expression of SMAD3 [8].
11. In the case of p53-deficient lung cancer cells, USP7 serves as a tumor modulator by acting as a de-monoubiquitinase for SMAD3 [8].

12. The BMP pathway promotes the progression of primary prostate cancer (PCa), and the inhibition of BMP signaling is associated with PCa development in PTEN-deficient mice. The TGFbeta and BMP pathways converge on SMAD4, with TGFbeta promoting PCa progression and BMP signaling inhibiting inflammation-related pathways [9].

Overall, SMAD4 is involved in various signaling pathways and genetic alterations in different types of cancers, including colon cancer, pancreatic neoplasms, and prostate cancer. The interplay between SMAD4-dependent and independent signaling pathways and its relationship with other genetic alterations have implications for tumor behavior and potential therapeutic strategies.

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