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Roles of DKK3 in cellular adhesion, motility, and invasion through extracellular interaction with TGFBI
Junko Kano1, Hongxin Wang2, Han Zhang2
1Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Japan.
Abstract:
Dickkopf-related protein (DKK) 3, a member of the DKK family, is a secreted glycoprotein that acts as a modulator of Wnt signaling in organogenesis and carcinogenesis. Recent studies have demonstrated that DKK3 has a variety of functions, suggesting that it plays roles not only in tumorigenesis, but also tumor neovascularization, prostatic acinus formation, cardiac vascular remodeling, renal and cardiac fibrosis, and immunological activity. The function of DKK3 is therefore of great interest, but details of the receptors and mechanisms involved have remained unclear. Here, we focused on the extracellular function of DKK3 as a secreted protein, and identified transforming growth factor beta induced protein ig-h3 (TGFBI) as a secreted protein interacting with DKK3. To investigate the function of these secreted proteins, we employed an in vitro cell model involving human hepatocellular carcinoma cells, human embryonic kidney cells, or non-neoplastic hepatocyte cells. We showed that DKK3 functions as an extracellular matrix-like molecule supporting adhesion, motility, and invasion, and that its interaction with TGFBI inhibits the functions of secreted DKK3 in cells expressing both proteins. These results suggest that this extracellular interaction between DKK3 and TGFBI modulates cell adhesion and motility through focal adhesion kinase signaling, and that this might serve as a potential therapeutic target in the context of cancer invasion and metastasis.
Insights
Dickkopf-related protein 3 (DKK3) supports cell adhesion and invasion. Its interaction with transforming growth factor beta induced protein ig-h3 (TGFBI) inhibits these functions, offering a potential therapeutic target for cancer metastasis.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Dickkopf-related protein 3 (DKK3) is a secreted glycoprotein modulating Wnt signaling in development and disease.
- DKK3 exhibits diverse roles in tumorigenesis, angiogenesis, fibrosis, and immunity, but its receptors and mechanisms remain unclear.
- Understanding the extracellular functions of DKK3 is crucial for elucidating its biological significance.
Purpose of the Study:
- To identify secreted proteins interacting with DKK3.
- To investigate the extracellular function of DKK3 and its interaction with identified partners.
- To explore the therapeutic potential of the DKK3-TGFBI interaction in cancer.
Main Methods:
- Utilized an in vitro cell model with human hepatocellular carcinoma, human embryonic kidney, and non-neoplastic hepatocyte cells.
- Identified transforming growth factor beta induced protein ig-h3 (TGFBI) as a DKK3-interacting protein.
- Analyzed the impact of the DKK3-TGFBI interaction on cell adhesion, motility, and invasion via focal adhesion kinase signaling.
Main Results:
- DKK3 functions as an extracellular matrix-like molecule promoting cell adhesion, motility, and invasion.
- The interaction between DKK3 and TGFBI inhibits the pro-adhesive and pro-migratory functions of DKK3.
- This extracellular interaction modulates cell behavior through focal adhesion kinase signaling.
Conclusions:
- The interaction between extracellular DKK3 and TGFBI inhibits DKK3-mediated cell adhesion and motility.
- This DKK3-TGFBI interaction represents a novel regulatory mechanism for cell behavior.
- The DKK3-TGFBI pathway presents a potential therapeutic target for inhibiting cancer invasion and metastasis.
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