Alpha V integrin prolongs collagenase production through Jun activation binding protein 1.
Robust expression of alphav integrin and matrix metalloproteinase 1 (MMP1) plays an important role in cancer metastasis and wound healing. A patient with an abnormal scar that appeared stretched and thinned out was found to have fibroblasts that overexpressed alphav integrin; therefore, a relationship between alphav integrin expression and MMP1 production was sought. A yeast 2 hybrid screen revealed alphav integrin interacts with jun activation binding domain-1 (JAB1). Mesenchymal-derived cells were transfected with the alphav integrin gene and incorporated into collagen lattices. Transfected cells maximally contracted collagen lattices beginning on day 5, whereas control transfected cells did not contract lattices. Late-phase collagen lattice contraction was inhibited by a pan-MMP inhibitor, BB4. Overexpression of alphav correlated with enhanced MMP1 transcription, as determined by a luciferase assay (P < or = 0.05). Diminution of JAB1 with JAB1 antisense abolished alphav integrin up-regulation of MMP1. We conclude alphav integrin signals through JAB1 to prolong MMP1 production and that this signaling pathway in fibroblasts may lead to abnormal scarring.
Levinson
Howard
H
Division of Plastic Surgery, M.S. Hershey Medical Center, Hershey, PA, USA. hlev1@yahoo.com
Sil
Alok K
AK
Conwell
John E
JE
Hopper
James E
JE
Ehrlich
H Paul
HP
D000075686:COP9 Signalosome Complex; D017364:Collagenases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D039564:Integrin alphaV / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000235:genetics; D020781:Matrix Metalloproteinase 1 / Q000502:physiology*; D010447:Peptide Hydrolases; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection; D014945:Wound Healing / Q000502:physiology*
D004268:DNA-Binding Proteins; D039564:Integrin alphaV; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; D008156:Luciferases; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D017364:Collagenases; D020781:Matrix Metalloproteinase 1