An Eph receptor regulates integrin activity through R-Ras.
The ability of integrins to mediate cell attachment to extracellular matrices and to blood proteins is regulated from inside the cell. Increased ligand-binding activity of integrins is critical for platelet aggregation upon blood clotting and for leukocyte extravasation to inflamed tissues. Decreased adhesion is thought to promote tumor cell invasion. R-Ras, a small intracellular GTPase, regulates the binding of integrins to their ligands outside the cell. Here we show that the Eph receptor tyrosine kinase, EphB2, can control integrin activity through R-Ras. Cells in which EphB2 is activated become poorly adherent to substrates coated with integrin ligands, and a tyrosine residue in the R-Ras effector domain is phosphorylated. The R-Ras phosphorylation and loss of cell adhesion are causally related, because forced expression of an R-Ras variant resistant to phosphorylation at the critical site made cells unresponsive to the anti-adhesive effect of EphB2. This is an unusual regulatory pathway among the small GTPases. Reduced adhesiveness induced through the Eph/R-Ras pathway may explain the repulsive effect of the Eph receptors in axonal pathfinding and may facilitate tumor cell invasion and angiogenesis.
Zou
J X
JX
Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, USA.
Wang
B
B
Kalo
M S
MS
Zisch
A H
AH
Pasquale
E B
EB
Ruoslahti
E
E
D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002461:Cell Line, Transformed; D002645:Chickens; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D036183:Receptor, EphB2; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D016023:Integrins; D011993:Recombinant Fusion Proteins; D020794:Receptor Protein-Tyrosine Kinases; D036183:Receptor, EphB2; D018631:ras Proteins