Cross-talk between RhoGTPases and stress activated kinases for matrix metalloproteinase-9 induction in response to keratinocytes injury.
Cell migration and extracellular matrix remodeling are two essential processes of wound healing, regulated by extracellular metalloproteinases such as matrix metalloproteinase-2 (Gelatinase A) and matrix metalloproteinase-9 (Gelatinase B). Expression of matrix metalloproteinase-9 is deregulated in numerous wound healing pathologies. To date the mechanisms regulating matrix metalloproteinase-9 during normal wound healing are poorly documented. Using both primary cultures of normal human keratinocytes and a wounding device especially designed to dissect the molecular events during the healing process in vitro, we show that matrix metalloproteinase-9 is stimulated by injury in normal human keratinocytes. This upregulation results from the mechanical stress created by injury and not from a soluble factor, secreted by wounded normal human keratinocytes. We also demonstrate that the Rho family of small GTPases, p38[MAPK] and JNK together play a key part in the signaling pathways controlling the stimulation of matrix metalloproteinase-9 in wounded cells. We provide lines of evidence indicating that in wounded keratinocytes, upregulation of matrix metalloproteinase-9 depends on two distinct pathways. The first involves Rac1 and/or Cdc42 that control the activation of p38[MAPK]. The second depends on RhoA activation that is required for stimulation of JNK.
Turchi
Laurent
L
INSERM U 385, Nice, France.
Chassot
Anne-Amandine
AA
Bourget
Isabelle
I
Baldescchi
Christine
C
Ortonne
Jean Paul
JP
Meneguzzi
Guerrino
G
Lemichez
Emmanuel
E
Ponzio
Gilles
G
D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000293:injuries*; D012995:Solubility; D014945:Wound Healing / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D012333:RNA, Messenger; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D020741:rho GTP-Binding Proteins