Interactions between Eph receptor tyrosine kinases (RTKs) and membrane-anch
ored ephrin ligands critically regulate axon pathfinding and development of
the cardiovascular system, as well as migration of neural cells. Similar t
o other RTKs, ligand-activated Eph kinases recruit multiple signalling and
adaptor proteins, several of which are involved in growth regulation(1,2).
However, in contrast to other RTKs, activation of Eph receptors fails to pr
omote cell proliferation(3,4) or to transform rodent fibroblasts(5), indica
ting that Eph kinases may initiate signalling pathways that are distinct fr
om those transmitted by other RTKs. Here we show that stimulation of endoge
nous EphA kinases with ephrin-A1 potently inhibits the Ras/MAPK cascade in
a range of cell types, and attenuates activation of mitogen-activated prote
in kinase (MAPK) by receptors for platelet-derived growth factor (PDGF), ep
idermal growth factor (EGF) and Vascular endothelial growth factor (VEGF).
In prostatic epithelial cells and endothelial cells, but not fibroblasts, t
reatment with ephrin-A1 inhibits cell proliferation. Our results identify E
phA kinases as negative regulators of the Ras/MAPK pathway that exert anti-
mitogenic functions in a cell-type-specific manner.