SMAD4: A Drug Target and Biomarker (G4089)

Target Name: SMAD4

NCBI ID: G4089

SMAD4

SMAD4: A Drug Target and Biomarker

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. It consists of three main domains: the N-terminal MH1 domain, the C-terminal MH2 domain, and the linker region between them. 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.

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.

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

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

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. Upon BMP stimulation, activated Smads, including SMAD4, bind to reachable consensus sequences, and stage-specific Smad partners regulate the induction of fate-specific genes.

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.

In advanced colon cancer, both activin and TGFbeta signaling pathways utilize SMAD4 to regulate the upregulation of p21, a protein involved in growth suppression.

However, in colon cancer, there is ligand-specific SMAD4-independent signaling that utilizes distinct mitogenic signaling pathways.
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.

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.
In contrast, colon cancers with loss of nuclear p21 may benefit from activin, TGFbeta, or combination inhibitory therapy.

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.

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.

Mutations in TP53 and SMAD4 are associated with malignant transformation in mucinous cystic adenomas of the pancreas.
Loss of p16 expression increases as IPMNs progress from non-invasive to invasive disease.

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.

In the case of p53-deficient lung cancer cells, USP7 serves as a tumor modulator by acting as a de-monoubiquitinase for SMAD3.

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.

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.

Protein Name: SMAD Family Member 4

Functions: In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator

The "SMAD4 Target / Biomarker Review Report" is a customizable review of hundreds up to thousends of related scientific research literature by AI technology, covering specific information about SMAD4 comprehensively, including but not limited to:
•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
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•   the target screening and validation;
•   expression level;
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The report is helpful for project application, drug molecule design, research progress updates, publication of research papers, patent applications, etc. If you are interested to get a full version of this report, please feel free to contact us at BD@silexon.ai

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