More About Wnt Inhibitors: Attention to Tumor Regulator DKK1

Dickkopf-1 (DKK1), is a protein that plays a critical role in regulating the Wnt signaling pathway, which is involved in various cellular processes, including cell proliferation, differentiation, and embryonic development. It is an important antagonist of the Wnt pathway, meaning that it inhibits Wnt signaling by binding to specific receptors and preventing the activation of downstream signaling molecules.

The structure of DKK1 is defined by its amino acid sequence, and it forms a specific three-dimensional conformation through folding and interactions of its constituent amino acids. The protein is composed of 266 amino acids, and its molecular weight is approximately 28 kDa. There are primary, secondary, tertiary, and quaternary structures of DKK1.

Primary structure: The regions that are important for its biological activity and interaction with other molecules.

Secondary structure: The local folding patterns of the amino acid backbone, including alpha-helices and beta-sheets. These structural elements contribute to the overall stability and function of the protein.

Tertiary structure: The three-dimensional arrangement of the entire polypeptide chain, including the interactions between different regions of the protein. This higher-order folding is crucial for the protein's ability to interact with its binding partners, such as Wnt receptors, and exert its inhibitory function on the Wnt signaling pathway.

Quaternary structure: The association of multiple DKK1 protein subunits, if applicable, to form a larger functional complex. DKK1 is known to interact with other proteins to modulate Wnt signaling, so its quaternary structure may involve the formation of dimers or higher-order oligomers.

Understanding the structure of DKK1 at the atomic level can provide valuable insights into its mechanism of action and its potential as a therapeutic target for various diseases, including cancer and bone disorders.

The Wnt signaling pathway is a complex network of proteins that control various cellular processes, including cell growth, differentiation, and tissue development. It has two main branches: the canonical Wnt pathway (also known as the Wnt/β-catenin pathway) and the non-canonical Wnt pathway.

A complete regulatory process of DKK1 usually includes: Wnt binding, DKK1 binding, inhibition of Wnt signaling, nuclear translocation of b-catenin, and suppression of target gene expression, togetherly five steps:

In the absence of Wnt ligands, a protein complex called the destruction complex is formed. This complex includes proteins such as Axin, APC (Adenomatous Polyposis Coli), GSK-3β (Glycogen Synthase Kinase-3β), and others. The destruction complex phosphorylates β-catenin, a key component of the canonical Wnt pathway, marking it for degradation by the proteasome.

When DKK1 is present and binds to the Wnt co-receptor LRP5/6 (Low-Density Lipoprotein Receptor-Related Protein 5/6) together with Kremen, it forms a complex that interferes with the interaction between the Wnt ligands and their receptors. This prevents the activation of the canonical Wnt pathway.

By interfering with the binding of Wnt ligands to their receptors, DKK1 blocks the signal that would normally lead to the inactivation of the destruction complex. As a result, β-catenin is not targeted for degradation and can accumulate in the cytoplasm.

Accumulated β-catenin can then translocate into the nucleus, where it forms a complex with TCF/LEF (T-cell Factor/Lymphoid Enhancer-Binding Factor) transcription factors. This complex activates the transcription of target genes that promote cell proliferation and survival.

DKK1 inhibits the nuclear translocation of β-catenin and its interaction with TCF/LEF, leading to a reduced expression of target genes that are normally activated by the canonical Wnt pathway.

The role of DKK1 in cancers is complex and can vary depending on the specific type of cancer and its microenvironment. In some cases, DKK1 acts as a tumor suppressor, while in others, it can promote tumor growth and progression. The dual role of DKK1 in cancer is attributed to its interactions with the Wnt signaling pathway.

In certain cancers, DKK1 acts as a tumor suppressor by inhibiting the Wnt/β-catenin signaling pathway. By blocking the canonical Wnt pathway, DKK1 helps to prevent the uncontrolled growth and proliferation of cancer cells. In this context, DKK1 expression is often downregulated in cancer cells compared to normal tissues, which allows for increased Wnt signaling and contributes to tumor development.

Conversely, in some cancers, DKK1 expression is upregulated, and it can promote tumor growth and metastasis through non-canonical Wnt signaling pathways or Wnt-independent mechanisms. For example, in certain types of bone metastases, DKK1 is produced by cancer cells, and it leads to the inhibition of osteoblasts, the cells responsible for bone formation, resulting in bone degradation and tumor growth.

DKK1 and Gastric Cancer

In gastric cancer, DKK1 expression is often upregulated compared to normal gastric tissue. The increased expression of DKK1 can disrupt the balance of Wnt signaling, leading to alterations in cell proliferation, migration, and differentiation, which are critical processes in cancer development. DKK1 can activate non-canonical Wnt signaling pathways and influence other cellular processes independent of the canonical Wnt/β-catenin pathway. High levels of DKK1 expression in gastric cancer have been linked to more advanced disease stages and poor prognosis. It may serve as a potential biomarker for predicting disease progression and patient outcomes.

DKK1 and Colorectal Cancer

In normal colorectal tissue, DKK1 acts as an antagonist of the Wnt pathway, inhibiting Wnt signaling and maintaining a balance that prevents uncontrolled cell proliferation. However, in colorectal cancer, the decreased expression of DKK1 allows for enhanced Wnt signaling, leading to increased activity of the Wnt/β-catenin pathway. Enhanced Wnt/β-catenin signaling in colorectal cancer contributes to the progression of the disease. It promotes cell proliferation, survival, and migration, which are critical factors in cancer development and metastasis. Consequently, the reduced levels of DKK1 in CRC contribute to the dysregulation of the Wnt pathway and support tumor growth and progression.

DKK1 and Other Diseases

In addition to its roles in cancer, DKK1 has been associated with several other diseases and conditions. Some of these non-cancer-related diseases where DKK1 plays a significant role include:

Osteoporosis: DKK1 is a key regulator of bone metabolism. It inhibits the Wnt/β-catenin signaling pathway in osteoblasts, which are bone-forming cells. By doing so, DKK1 suppresses bone formation and turnover, leading to a negative impact on bone density. Elevated levels of DKK1 have been found in individuals with osteoporosis, suggesting a potential role in the pathogenesis of this condition.

Alzheimer's Disease (AD): DKK1 has been implicated in AD due to its involvement in synaptic plasticity and neuronal survival. In AD, there is evidence that DKK1 may contribute to the impairment of synaptic function and neuronal degeneration. DKK1 has been found to accumulate in the brains of AD patients, and its expression may be influenced by factors associated with neuroinflammation and oxidative stress.

Rheumatoid Arthritis (RA): In RA, DKK1 is involved in the regulation of bone erosion and joint destruction. Elevated levels of DKK1 have been observed in the synovial tissue and fluid of RA patients, and it has been shown to promote osteoclast formation and bone resorption.

Ankylosing Spondylitis (AS): AS is a type of inflammatory arthritis that primarily affects the spine and sacroiliac joints. DKK1 is thought to contribute to the pathological bone formation characteristic of AS. It promotes the differentiation of osteoblasts, which leads to excessive bone formation and ankylosis (fusion) of the joints.

Cardiovascular Disease: DKK1 has been linked to cardiovascular diseases, including atherosclerosis and calcific aortic valve disease. It may play a role in vascular calcification and contribute to the progression of these conditions.

Diabetes and Metabolic Disorders: DKK1 has been associated with insulin resistance and glucose metabolism in certain metabolic disorders, such as obesity and type 2 diabetes. It may influence the function of adipose tissue and insulin sensitivity.

Beta Lifescience provides a series of DKK1 related proteins that are suitable for various applications, including animal immunology, targeted drugs, functional evaluation, and quality control, among other different stages.

Recombinant Human DKK-1 (N-8His)

Recombinant Human DKK-1 (C-6His)

Recombinant Human DKK-1 (C-Fc)

Biotinylated Human DKK-1 (C-Avi-6His)

Recombinant Human DKK-3 (C-6His)

[1] Chu, Hang Yin, et al. "Dickkopf-1: A promising target for cancer immunotherapy." Frontiers in Immunology 12 (2021): 658097.

[2] Fulciniti, Mariateresa, et al. "Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma." Blood, The Journal of the American Society of Hematology 114.2 (2009): 371-379.

[3] https://www.sec.gov/Archives/edgar/data/1509745/000110465921117855/tm2128111d1_ex99-2.htm