Extracellular Interactions between Fibulins and Transforming Growth Factor (TGF)-β in Physiological and Pathological Conditions

Abstract

Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell–matrix interactions, including thrombospondins, SPARC (Secreted Protein Acidic and Rich in Cystein), tenascins, osteopontin, periostin, and fibulins. Fibulin family members consist of eight ECM glycoproteins characterized by a tandem array of calcium-binding epidermal growth factor-like modules and a common C-terminal domain. Fibulins not only participate in structural integrity of basement membrane and elastic fibers, but also serve as mediators for cellular processes and tissue remodeling as they are highly upregulated during embryonic development and certain disease processes, especially at the sites of epithelial–mesenchymal transition (EMT). Emerging studies have indicated a close relationship between fibulins and TGF-β signaling, but each fibulin plays a different role in a context-dependent manner. In this review, regulatory interactions between fibulins and TGF-β signaling are discussed. Understanding biological roles of fibulins in TGF-β regulation may introduce new insights into the pathogenesis of some human diseases.

<p>EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating MMPs</p>

“…11,12 Defects of EFEMP2 in patients have been linked to many diseases, such as autosomal recessive cutis laxa syndrome, aneurysms and tortuosity of the large arteries, developmental emphysema, diaphragmatic and inguinal hernia, joint laxity and cancer. [13][14][15] The role of EFEMP2 in tumorigenesis has not yet been fully elucidated, both carcinogenic and anti-carcinogenic effects have been reported. High expression of EFEMP2 was associated with tumor progress and poor prognosis in cervical carcinoma, 16 ovarian carcinoma, 17 glioblastoma 18 and osteosarcoma.…”

The molecular interaction of ADAMTS-1 and fibulin-1 and its potential contribution to breast cancer biology

“…Fibulin-1 can interact with various ECM components, including known ADAMTS-1 substrates, such as nidogen-1 and versican [2,21,27] . Fibulin-1 has also been implicated in cellular transformation and, similar to ADAMTS-1, can behave as both a tumorigenic factor or tumor suppressor depending on the tissue environment [23] .…”

“…The extracellular environment is a dynamic niche in which multiple molecular interactions occur that govern cell fate. Several families of extracellular proteins function in this molecular dance, influencing cell properties and thus regulating either physiological or pathological processes [1,2] . In addition, stromal cells are considered especially important in the extracellular environment as they induce extracellular modifications that can promote dysfunction in processes such as in cancer progression [3] .…”

Silibinin inhibits epithelial‑mesenchymal transition of renal cell carcinoma through autophagy‑dependent Wnt/β‑catenin signaling

“…2A and B, SB increased the expression of E-cadherin and decreased the expression of the mesenchymal markers N-cadherin and vimentin in both a concentration-and time-dependent manner. To further demonstrate the effects of SB on EMT, cells were treated with TGF-β1, a well-known EMT inducer (21). TGF-β1-induced EMT, as determined by an increase in N-cadherin and vimentin expression and decrease in E-cadherin expression, and this was prevented by treatment with SB (Fig.…”