Integrin alpha3beta1 potentiates TGFbeta-mediated induction of MMP-9 in immortalized keratinocytes.
Transforming growth factor-beta (TGFbeta) signaling pathways regulate a number of keratinocyte functions during epidermal carcinogenesis and wound healing, including proliferation, survival, and migration. TGFbeta can induce expression of the matrix metalloproteinase-9 (MMP-9), which has critical roles in promoting extracellular matrix remodeling and angiogenesis during tumorigenesis and tissue repair. Integrin alpha3beta1 is a cell adhesion receptor for laminin-332/laminin-5 with important roles in the survival and motility of epidermal keratinocytes. We previously reported that alpha3beta1 induces the expression of MMP-9 in immortalized keratinocytes. In this study, we show that endogenous TGFbeta is required for maximal MMP-9 expression, and that alpha3beta1 is required for full induction of MMP-9 protein and mRNA in response to TGFbeta. This regulation was not observed in non-immortalized, primary keratinocytes, indicating that coordinate regulation of MMP-9 by alpha3beta1 and TGFbeta is a property of immortalized cells. Alpha3beta1 did not regulate endogenous TGFbeta gene expression, TGFbeta bioavailability, or TGFbeta-Smad signaling. However, the combined inductive effects of TGFbeta and alpha3beta1 on MMP-9 were suppressed by a Src family kinase (SFK) inhibitor, indicating involvement of a SFK pathway. These findings provide early evidence of a role for alpha3beta1 in augmenting TGFbeta-mediated induction of MMP-9 in immortalized or transformed keratinocytes during skin carcinogenesis.
Lamar
John M
JM
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208-3479, USA.
Iyer
Vandana
V
DiPersio
C Michael
CM
D000818:Animals; D002461:Cell Line, Transformed; D000078404:Epidermal Cells; D005109:Extracellular Matrix / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D011905:Genes, ras / Q000502:physiology; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D039201:Integrin alpha3beta1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D020780:Matrix Metalloproteinase 9