Dissecting STAT3 A Key Regulator of Signal Transduction

What is STAT？

Signal transducer and activator of transcription (STAT) proteins belong to the transcription factor class and are triggered by various stimuli like cytokines and growth factors. When exposed to diverse cytokine signals in the cytoplasm, STATs undergo tyrosine phosphorylation, leading to their activation. Following this activation, they relocate to the nucleus, where they bind to specific targets and serve as transcription factors[1-2]. STATs play a vital role in various physiological processes, such as cell proliferation, apoptosis, division, and differentiation[3].

While STAT activation is closely controlled in healthy cells to prevent uncontrolled gene expression, prolonged activation in cancer cells can lead to detrimental effects like drug resistance and poor prognosis. The human STAT family comprises seven proteins: STAT-1, −2, −3, −4, −5A, −5B, and −6. The genes encoding these proteins are situated on chromosomes 2 (STAT-1 and −4), 12 (STAT-2 and −6), and 17 (STAT-3, −5A, and −5B)[4]. Among these members, STAT-3 and −5 are particularly associated with tumor progression.

Persistent activation of STAT-3 or STAT-5, especially STAT-3, governs several functions like proliferation, cell cycle progression, apoptosis, angiogenesis, and immune evasion[5-6]. As a result, STAT-3 significantly contributes to tumor growth and survival, particularly due to its role in stromal cells. These cells involve immune cell recruitment within the tumor microenvironment, fostering tumor expansion. This recognition has established STAT-3 as a promising target for cancer therapy[7-8].

Understanding the Structure and Function of STAT3

STAT3, an 89 kDa protein, is encoded by the STAT3 gene and consists of 770 amino acids. The protein is composed of six functional domains that play a crucial role in its functioning. The NH2-terminal domain is responsible for higher order complex formation, followed by the coiled-coil domain that interacts with co-regulators and transcription factors. The DNA binding domain has a sequence specificity for an interferon gamma (INFγ) activated sequence (GAS) present in the promoter region of specific genes. The linker domain is located directly before the Src homology-2 (SH2) domain, which mediates receptor recruitment and STAT3 dimerization via intermolecular phosphorylated tyrosine-SH2 interactions. The transcription activation domain (TAD), located in the COOH-terminal region, is where regulatory phosphorylation occurs.

STAT3 exists in two main isoforms, STAT3α and STAT3β. STAT3β is the truncated form of STAT3α, lacking the 55-residue C-terminal transactivation domain. Although STAT3β can be phosphorylated at the tyrosine 705 (Y705) residue, it lacks serine 727 (S727). Despite this, STAT3β can still bind to DNA as a homo- or heterodimer (with STAT3α or other transcription factors). However, the role of STAT3β in the heart is unclear.

The primary function of STAT3 is to regulate gene transcription. The protein undergoes several post-translational modifications, including acetylation, phosphorylation, methylation, ubiquitination, s-nitrosylation, and glutathionylation, which have functional consequences. Recent evidence suggests that S-palmitoylation of STAT3 promotes its dimerization and transcriptional activation.

Overall, understanding the structure and function of STAT3 is crucial for understanding its role in gene transcription and cellular signaling pathways.

Advances in Targeting STAT-3 for Antitumor Therapeutics

STAT-3 plays a crucial role in various cellular processes, including the cell cycle, cell proliferation, cellular apoptosis, tumorigenesis, and the regulation of the tumor niche. While STAT-3 activation is tightly regulated in healthy cells, abnormal activation of STAT-3 can lead to the development of numerous diseases, including various types of cancer. Studies have shown that high-frequency abnormal activation of STAT-3 is associated with brain, lung, pancreatic, renal, colorectal, endometrial, cervical, ovarian, breast, and prostate cancer, as well as melanoma, glioma, head and neck squamous cell carcinoma, lymphoma, and leukemia.

Research has demonstrated that targeted deletion of STAT-3 in intestinal epithelial cells significantly inhibits tumor occurrence and progression in a colitis-associated cancer model. Furthermore, STAT-3 inhibits the synthesis of p53, reducing its protective effect on genomic stability. Additionally, inflammatory mediators can increase the likelihood of DNA damage and gene mutation in parenchymal cells, and STAT-3 can reduce the tolerance of ovarian cancer cells to stress and damage. Activation of STAT-3 has also been found to activate miR-608, which inhibits the proliferation, migration, and invasiveness of lung cancer cells. Moreover, STAT-3 plays a critical role in the regulation of the tumor niche, as demonstrated by Annexin10's promotion of extrahepatic cholangiocarcinoma metastasis via the STAT-3 pathway.

Given the significant role of persistent STAT-3 activation in cell proliferation, differentiation, migration, and survival, researchers have focused on inhibiting the STAT-3 signaling pathway as a potential approach to cancer treatment. Previous attempts to inhibit receptor tyrosine kinases (RTKs) have led to the activation of STAT-3, limiting the therapeutic efficacy of certain small molecules targeting RTKs due to the development of drug resistance. Overcoming drug resistance is a major challenge in antitumor therapy, and targeting the STAT-3 pathway may help restore the efficacy of chemotherapeutic agents. While only one compound (BBI-608) targeting STAT-3 has been approved by the FDA for clinical use, several small molecules have shown promise in antagonizing the STAT-3 signaling pathway.

STAT3 Signaling Pathway

The STAT3 signaling pathway intricately oversees a myriad of biological processes, encompassing cell proliferation, differentiation, apoptosis, immune responses, and inflammatory reactions. This pathway's classic course comprises several pivotal steps, each contributing to its dynamic functionality.

1.Cytokine Receptor Activation: Instigating STAT3 Activation

The initiation of STAT3's activation primarily stems from cytokine receptor activation. Notably, diverse cytokines, such as interferons and interleukin-6 (IL-6), bind to their corresponding receptors, subsequently kickstarting the receptor tyrosine kinase activity.

2.Activation of Receptor Tyrosine Kinases: A Critical Facet

Cytokine receptor activation sets off the activation of their associated tyrosine kinases. This often transpires through receptor autophosphorylation or intricate interactions with other protein entities.

3.Phosphorylation of STAT3: Pivotal Modification

The phosphorylation of STAT3 emerges as a consequential outcome of activated receptor tyrosine kinases. This phosphorylation event leads to a conformational shift within STAT3, unveiling its activation domain.

4.STAT3 Dimerization: Fostering Collaborative Action

Phosphorylated STAT3 molecules bind with their counterparts through the SH2 domain, creating dimers. Dimerization exposes STAT3's activation domain, empowering it to engage in diverse protein interactions.

5.Translocation to the Nucleus: STAT3's Inner Journey

Dimerized STAT3 voyages into the nucleus, wherein it binds to DNA and exerts regulatory influence over the transcriptional activities of target genes by engaging with specific DNA sequences.

6.Transcriptional Control of Target Genes: Influencing Genetic Activity

Within the nucleus, DNA-bound STAT3 either activates or inhibits specific target genes' transcriptional activities. This intricate role often involves collaborations with transcription factors, co-activators, or co-repressors.

In general, the canonical STAT3 signaling pathway unfolds through a sequence of steps: cytokine receptor activation, receptor tyrosine kinase activation, STAT3 phosphorylation, STAT3 dimerization, nuclear translocation, and the nuanced transcriptional control of target genes. This pathway assumes a pivotal role in steering numerous biological processes through precise regulation.

Significance of Clinical Examination of STAT3

STAT3 plays an important role in cell signal transduction and regulation of immunity, inflammation, cell proliferation and differentiation. The clinical significance of STAT3 mainly includes the following aspects:

1. Immune system diseases: Abnormal activation of STAT3 is associated with a variety of immune system diseases, such as autoimmune diseases, inflammatory bowel disease, rheumatoid arthritis, etc. Clinical examination of STAT3 activity and expression levels can help diagnose and monitor the progression of these diseases.
2. Tumor: STAT3 plays an important role in tumorigenesis and development. Abnormally activated STAT3 is associated with the occurrence, metastasis and drug resistance of various tumors. Clinical examination of the expression and activation status of STAT3 can be used as a tumor prognostic indicator and therapeutic target.
3. Cardiovascular diseases: STAT3 plays an important role in the cardiovascular system and participates in processes such as cardiomyocyte protection, angiogenesis and repair. Clinical examination of STAT3 expression and activity can assess cardiovascular disease risk and prognosis.
4. Nervous system diseases: STAT3 is involved in neuroprotection, regeneration and neuroinflammation in the nervous system. Clinically examining the expression and activation status of STAT3 can help assess the severity and prognosis of neurological diseases.

In summary, clinical examination of STAT3 activity and expression levels can provide important biomarker information to help diagnose and treat a variety of diseases, predict disease progression and prognosis, and guide the selection of individualized treatments.

STAT3 Protein

Recombinant Human STAT3 Protein

Click here for more STAT3

Synonym : APRF, FLJ20882, MGC16063

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