title: Cdc42 inhibits ERK-mediated collagenase-1 (MMP-1) expression in collagen-activated human keratinocytes.
abstract: Following injury, keratinocytes switch gene expression programs from the one that promotes differentiation to the one that supports migration. A common feature of human wounds and ulcerations of any form is the expression of matrix metalloproteinase 1 (MMP-1; collagenase-1) by leading-edge basal keratinocytes migrating across the dermal or provisional matrix. Induction of MMP-1 occurs by signaling from the α2β1 integrin in contact with dermal fibrillar type I collagen, and the activity of MMP-1 is required for human keratinocytes to migrate on collagen. Thus, MMP-1 serves a critical role in the repair of damaged human skin. Here, we evaluated the mechanisms controlling MMP-1 expression in primary human keratinocytes from neonatal foreskin and adult female skin. Our results demonstrate that shortly following contact with type I collagen extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase were markedly activated, whereas c-Jun N-terminal kinase (JNK) phosphorylation remained at basal levels. ERK inhibition markedly blocked collagen-stimulated MMP-1 expression in keratinocytes. In contrast, inhibiting p38 or JNK pathways had no effect on MMP-1 production. Moreover, investigating the role of Rho GTPases revealed that Cdc42 attenuates MMP-1 expression by suppressing ERK activity. Thus, our data indicate that injured keratinocytes induce MMP-1 expression through ERK activation, and this process is negatively regulated by Cdc42 activity.
authors.affiliation: Center for Lung Biology, University of Washington, Seattle, Washington, USA; Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington, USA. Electronic address: mrohani@uw.edu.
authors.forename: Maryam G
authors.initials: MG
authors.lastname: Rohani
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Pilcher
authors.affiliation: Center for Lung Biology, University of Washington, Seattle, Washington, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Chen
authors.affiliation: Center for Lung Biology, University of Washington, Seattle, Washington, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Parks
mesh_terms: D000328:Adult; D002450:Cell Communication / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D024042:Collagen Type I / Q000378:metabolism*; D005260:Female; D052816:Foreskin / Q000166:cytology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000293:injuries; D012883:Skin Ulcer / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000502:physiology
chemical_list: C514543:ARHGAP31 protein, human; D024042:Collagen Type I; D020690:GTPase-Activating Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1