Background: Wound healing and scarring are driven by transforming growth factor-␤1 (TGF-␤1)-dependent fibroblast to myofibroblast differentiation. Results: Cell surface CD44 and epidermal growth factor receptor (EGFR) co-localize in lipid rafts to signal through mitogenactivated protein kinase 1/2 (ERK1/2) and Ca 2ϩ /calmodulin kinase II (CaMKII). Conclusion: CD44 moves into lipid rafts in a TGF-␤1-and hyaluronan-dependent manner, co-localizes with EGFR, and triggers differentiation. Significance: This pathway presents novel targets for the therapy of wound-healing and fibrosis.

Ataxia-telangiectasia and rad3 (ATR)-related Seckel syndrome is associated with growth retardation and premature aging features. ATR-Seckel fibroblasts have a reduced replicative capacity in vitro and an aged morphology that is associated with activation of stress-associated p38 mitogen-activated protein kinase and phosphorylated HSP27. These phenotypes are prevented using p38 inhibitors, with replicative capacity restored to the normal range. However, this stressed phenotype is retained in telomerase-immortalized ATR-Seckel fibroblasts, indicating that it is independent of telomere erosion. As with normal fibroblasts, senescence in ATR-Seckel is bypassed by p53 abrogation. Young ATR-Seckel fibroblasts show elevated levels of p21WAF1, p16INK4A, phosphorylated actin-binding protein cofilin, and phosphorylated caveolin-1, with small molecule drug inhibition of p38 reducing p16INK4A and caveolin-1 phosphorylation. In conclusion, ATR-Seckel fibroblasts undergo accelerated aging via stress-induced premature senescence and p38 activation that may underlie certain clinical features of Seckel syndrome, and our data suggest a novel target for pharmacological intervention in this human syndrome.