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Extracellular matrix-associated transforming growth factor-beta: role in cancer cell growth and invasion
J Taipale1, J Saharinen, J Keski-Oja
1Department of Virology, Haartman Institute, University of Helsinki, Finland.
Abstract:
Growth factors of the transforming growth factor-beta (TGF-beta) family inhibit the proliferation of epithelial, endothelial, and hematopoietic cells, and stimulate the synthesis of extracellular matrix components. TGF-beta s are secreted from cells in high-molecular-mass protein complexes that are composed of three proteins, the mature TGF-beta-dimer, the TGF-beta propeptide dimer, or latency-associated protein (LAP), and the latent TGF-beta binding protein (LTBP). Mature TGF-beta is cleaved from its propeptide during secretion, but the proteins remain associated by noncovalent interactions. LTBP is required for efficient secretion and processing of latent TGF-beta and it binds to LAP via disulfide bond(s). LTBP is a component of extracellular matrix microfibrils, and it targets the latent TGF-beta complex to the extracellular matrix. TGF-beta signaling is initiated by proteolytic cleavage of LTBP that results in the release of the latent TGF-beta complex from the extracellular matrix. TGF-beta is activated by dissociation of LAP from the mature TGF-beta. Subsequent signaling involves binding of active TGF-beta to its type II cell surface receptors, which phosphorylate and activate type I TGF-beta receptors. Type I receptors, in turn, phosphorylate cytoplasmic transcriptional activator proteins Smad2 and Smad3, inducing their translocation to the nucleus. Recent evidence suggests that acquisition of resistance to TGF-beta growth inhibition plays a major role in the progression of epithelial and hematopoietic cell malignancies. The role of secretion of TGF-beta in tumorigenesis is more complex. The secretion of TGF-beta s by tumor cells may contribute to autocrine growth inhibition, but on the other hand, it may also promote invasion, metastasis, angiogenesis, and even immunosuppression. Tumor cells may also fail to deposit LTBP:TGF-beta complexes to the extracellular matrix. The elucidation of the mechanisms of the release of TGF-beta from the matrix and its subsequent activation aids the understanding of the pathophysiologic roles of TGF-beta in malignant growth, and allows the development of therapeutic agents that regulate the activity of TGF-beta.
Insights
Transforming growth factor-beta (TGF-beta) regulates cell growth and matrix synthesis. Understanding TGF-beta release from extracellular matrix and its activation is key to developing cancer therapies.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor-beta (TGF-beta) family members regulate cell proliferation and extracellular matrix production.
- TGF-beta is secreted in latent complexes involving latency-associated protein (LAP) and latent TGF-beta binding protein (LTBP).
- LTBP targets latent TGF-beta to the extracellular matrix, regulating its availability.
Purpose of the Study:
- To elucidate the mechanisms of TGF-beta release from the extracellular matrix.
- To understand the activation process of TGF-beta signaling.
- To explore the pathophysiologic roles of TGF-beta in malignant growth and identify therapeutic targets.
Main Methods:
- Analysis of TGF-beta secretion and complex formation.
- Investigation of LTBP's role in TGF-beta latency and matrix targeting.
- Study of TGF-beta signaling pathway activation via Smad proteins.
- Examination of TGF-beta resistance in epithelial and hematopoietic malignancies.
Main Results:
- LTBP is essential for efficient secretion, processing, and extracellular matrix deposition of latent TGF-beta.
- Proteolytic cleavage of LTBP releases the latent TGF-beta complex from the matrix.
- TGF-beta activation involves LAP dissociation, receptor binding, and Smad2/3 phosphorylation.
- Resistance to TGF-beta growth inhibition is implicated in cancer progression.
Conclusions:
- Elucidating TGF-beta release and activation mechanisms enhances understanding of its role in cancer.
- Dysregulation of TGF-beta secretion and matrix interaction contributes to tumorigenesis.
- Targeting TGF-beta regulation offers potential therapeutic strategies for cancer treatment.