Keloid fibroblast responsiveness to epidermal growth factor and activation of downstream intracellular signaling pathways.
Keloids, which overgrow the boundaries of the original injury, represent aberrations in the fundamental process of wound healing that include over-abundant cell in-migration, cell proliferation, and inflammation, as well as increased extracellular matrix synthesis and defective remodeling. To understand the key events that result in the formation of these abnormal scars would open new avenues for better understanding of excessive repair, and might provide new therapeutic options. We examined epidermal growth factor receptor (EGFR)-induced cell motility in keloid fibroblasts, as this receptor initiates cell migration during normal wound repair. We show that keloid fibroblasts respond to EGF-induced cell migration but the response is somewhat diminished compared to normal adult fibroblasts (approximately 30% reduced); the mitogenic response was similarly blunted (approximately 5% reduced). Keloid fibroblasts express near normal levels of EGFR (82%), but show a much more attenuated activation of EGFR itself and the motility-associated phospholipase C-gamma. This was reflected in part by rapid loss of EGFR upon exposure to EGF. Interestingly, while extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) activation was relatively robust in keloid fibroblasts, the downstream triggering of the motility-associated calpain activity was blunted. This was reflected by high cell-substratum adhesiveness in the keloid fibroblasts. Thus, the blunted migratory response to EGF noted in keloid fibroblasts appears due to limited activation of two important biochemical switches for cell motility.
Satish
Latha
L
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Babu
Mary
M
Tran
Kien T
KT
Hebda
Patricia A
PA
Wells
Alan
A
D000328:Adult; D000368:Aged; D002154:Calpain / Q000502:physiology; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D002465:Cell Movement; D002648:Child; D004815:Epidermal Growth Factor / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D007627:Keloid / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D051966:Phospholipase C gamma; D010738:Type C Phospholipases / Q000502:physiology*
D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002154:Calpain