Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway.
Interactions between Eph receptor tyrosine kinases (RTKs) and membrane-anchored ephrin ligands critically regulate axon pathfinding and development of the cardiovascular system, as well as migration of neural cells. Similar to other RTKs, ligand-activated Eph kinases recruit multiple signalling and adaptor proteins, several of which are involved in growth regulation. However, in contrast to other RTKs, activation of Eph receptors fails to promote cell proliferation or to transform rodent fibroblasts, indicating that Eph kinases may initiate signalling pathways that are distinct from those transmitted by other RTKs. Here we show that stimulation of endogenous EphA kinases with ephrin-A1 potently inhibits the Ras/MAPK cascade in a range of cell types, and attenuates activation of mitogen-activated protein kinase (MAPK) by receptors for platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). In prostatic epithelial cells and endothelial cells, but not fibroblasts, treatment with ephrin-A1 inhibits cell proliferation. Our results identify EphA kinases as negative regulators of the Ras/MAPK pathway that exert anti-mitogenic functions in a cell-type-specific manner.
Miao
H
H
Rammelkamp Center for Research, MetroHealth Campus, Case Western Reserve University School of Medicine, 2500 MetroHealth Drive, Cleveland, Ohio 44109 USA.
Wei
B R
BR
Peehl
D M
DM
Li
Q
Q
Alexandrou
T
T
Schelling
J R
JR
Rhim
J S
JS
Sedor
J R
JR
Burnett
E
E
Wang
B
B
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D016228:Endothelial Growth Factors / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D036382:Ephrin-A1; D004815:Epidermal Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D015603:Keratinocytes / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011233:Precipitin Tests; D011471:Prostatic Neoplasms / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D036082:Receptor, EphA1; D036104:Receptor, EphA2; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D036382:Ephrin-A1; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004815:Epidermal Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D036082:Receptor, EphA1; D036104:Receptor, EphA2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins