The proliferation of fetal lung fibroblasts following severe neonatal lung injury is pathognomonic for bronchopulmonary dysplasia (BPD), a syndrome of high morbidity and mortality among premature infants. The incidence of BPD correlates with lung immaturity. Fetal lung fibroblast proliferation is regulated by growth factor activation of 46, 52, and 66 kDa Shc isoforms (Shc 46, Shc 52, and Shc 66, respectively). Shc 52 mediates cell proliferation through Ras-dependent and - independent pathways. Shc 66 is a dominant inhibitor of Ras activation. The function of Shc 46 is unclear. Shc 66 is highly expressed in fetal lung fibroblast precursors but disappears with lung maturation. Shc 66 expression is increased by premature delivery in an animal model of BPD. Shc 66 may therefore mediate the pathological proliferation of immature lung fibroblasts. Shc 66 is tyrosine phosphorylgted by both EGF and -TGF-beta signaling, but appears to assume its dominant inhibitory configuration only after EGF stimulation. These findings suggest that Shc 66 may have a Ras-independent ction which is activated by TGF- beta signaling. Because Shc 66 participates in both EGF and TGF-beta signaling, this isoform may also mediate an interaction between the EGF and TGF-beta signaling pathways. This project will correlate Shc isoform expression with cell proliferation, determine if Shc 66 mediates multiple signaling functions, and determine if Shc 66 confers feedback regulation of MAP kinase activity. Shc isoforms will be inducibly expressed in 3T3-Swiss cells and transiently expressed in primary fetal lung mesenchymal cells, after which EGF and TGF-beta mitogenesis will be assessed. These experiments will be repeated with Shc 66 mutants to determine if separate tyrosine sites mediate different functions. Feedback regulation of MAP kinase activity will be investigated by determining if Elk-1, a downstream mediator of MAP kinase, modulates Shc isoform expression. By determining how Shc 66 regulates the growth of fibroblast precursors in the fetal and preterm neonatal lung, new strategies may be developed to attenuate the pathological fibroblast proliferation of BPD.
| Lee, M K; Smith, S M; Banerjee, Maalika M et al. (2014) The p66Shc adapter protein regulates the morphogenesis and epithelial maturation of fetal mouse lungs. Am J Physiol Lung Cell Mol Physiol 306:L316-25 |
| Lee, Matt K; Pardoux, Cecile; Hall, Marie C et al. (2007) TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J 26:3957-67 |
