Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades.
Fibulin-5 (FBLN-5; also known as DANCE or EVEC) is an integrin-binding extracellular matrix protein that mediates endothelial cell adhesion; it is also a calcium-dependent elastin-binding protein that scaffolds cells to elastic fibers, thereby preventing elastinopathy in the skin, lung, and vasculature. Transforming growth factor-beta (TGF-beta) regulates the production of cytokines, growth factors, and extracellular matrix proteins by a variety of cell types and tissues. We show here that TGF-beta stimulates murine 3T3-L1 fibroblasts to synthesize FBLN-5 transcript and protein through a Smad3-independent pathway. Overexpression of FBLN-5 in 3T3-L1 cells increased DNA synthesis and enhanced basal and TGF-beta-stimulated activation of ERK1/ERK2 and p38 mitogen-activated protein kinase (MAPK). FBLN-5 overexpression also augmented the tumorigenicity of human HT1080 fibrosarcoma cells by increasing their DNA synthesis, migration toward fibronectin, and invasion through synthetic basement membranes. In stark contrast, FBLN-5 expression was down-regulated in the majority of metastatic human malignancies, particularly in cancers of the kidney, breast, ovary, and colon. Unlike its proliferative response in fibroblasts, FBLN-5 overexpression in mink lung Mv1Lu epithelial cells resulted in an antiproliferative response, reducing their DNA synthesis and cyclin A expression. Moreover, FBLN-5 synergizes with TGF-beta in stimulating AP-1 activity in Mv1Lu cells, an effect that was abrogated by overexpression of dominant-negative versions of either MKK1 or p38 MAPKalpha. Accordingly, both the stimulation and duration of ERK1/ERK2 and p38 MAPK by TGF-beta was enhanced in Mv1Lu cells expressing FBLN-5. Our findings identify FBLN-5 as a novel TGF-beta-inducible target gene that regulates cell growth and motility in a context-specific manner and affects protein kinase activation by TGF-beta. Our findings also indicate that aberrant FBLN-5 expression likely contributes to tumor development in humans.
Schiemann
William P
WP
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. schiemannwp@njc.org
Blobe
Gerard C
GC
Kalume
Dario E
DE
Pandey
Akhilesh
A
Lodish
Harvey F
HF
D016475:3T3 Cells; D000818:Animals; D015152:Blotting, Northern; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005354:Fibrosarcoma / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000166:cytology; D020935:MAP Kinase Signaling System; D013058:Mass Spectrometry; D051379:Mice; D008907:Mink; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010957:Plasmids / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism*; D012190:Retroviridae / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; C120769:Fbln5 protein, mouse; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D013936:Thymidine