N. Morino et al., Glomerular overexpression and increased tyrosine phosphorylation of focal adhesion kinase p125(FAK) in lupus-prone MRL/MP-lpr/lpr mice, IMMUNOLOGY, 97(4), 1999, pp. 634-640
Much progress has been made in understanding how mammalian cells receive a
diverse array of external stimuli and convert them into intracellular bioch
emical signals. Such efforts have identified a large number of signalling m
olecules. However, our knowledge is limited as to their pathophysiological
role in particular diseases. We demonstrate herein that an integrin-linked
signalling molecule, focal adhesion kinase p125(FAK) (FAK), is overexpresse
d in glomeruli of lupus-prone MRL/MP-lpr/lpr (MRL-lpr) mouse as compared to
its congeneic MRL-+/+ strain. Increased expression was specifically demons
trated in glomeruli but not in other tissues examined. The overexpression w
as observed in 16-week-old MRL-lpr mice with active nephritis, as well as i
n younger animals at 4 weeks of age. Thus, the upregulation of FAK clearly
preceded the clinical onset of nephritis. FAK in MRL-lpr glomeruli is highl
y tyrosine phosphorylated and is associated with adapter protein Grb2. Prev
ious in vitro studies have shown that the association of FAK/Grb2 links cel
l adhesion to the Pas pathway, which ultimately stimulates mitogen-activate
d protein (MAP) kinase, an important regulator of cell proliferation. In ac
cordance, we observed constitutive MAP kinase activation in MRL-lpr glomeru
li. Our findings suggest that signalling pathways involving FAK are activat
ed in MRL-lpr glomeruli, and are likely to play a role in the development a
nd progression of autoimmune-mediated murine nephritis.