EphrinB phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase.
Ephrins are cell surface-associated ligands for Eph receptors and are important regulators of morphogenic processes such as axon guidance and angiogenesis. Transmembrane ephrinB ligands act as "receptor-like" signaling molecules, in part mediated by tyrosine phosphorylation and by engagement with PDZ domain proteins. However, the underlying cell biology and signaling mechanisms are poorly understood. Here we show that Src family kinases (SFKs) are positive regulators of ephrinB phosphorylation and phosphotyrosine-mediated reverse signaling. EphB receptor engagement of ephrinB causes rapid recruitment of SFKs to ephrinB expression domains and transient SFK activation. With delayed kinetics, ephrinB ligands recruit the cytoplasmic PDZ domain containing protein tyrosine phosphatase PTP-BL and are dephosphorylated. Our data suggest the presence of a switch mechanism that allows a shift from phosphotyrosine/SFK-dependent signaling to PDZ-dependent signaling.
Palmer
Amparo
A
Max Planck Institute of Neurobiology, Am Klopferspitz 18A, D-82152 Martinsried, Germany.
Zimmer
Manuel
M
Erdmann
Kai S
KS
Eulenburg
Volker
V
Porthin
Annika
A
Heumann
Rolf
R
Deutsch
Urban
U
Klein
Rüdiger
R
D016475:3T3 Cells / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D036387:Ephrin-B1; D036388:Ephrin-B2; D006801:Humans; D008024:Ligands; D021962:Membrane Microdomains; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D036224:Receptor, EphB4; D036081:Receptors, Eph Family; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014469:Umbilical Arteries; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D004791:Enzyme Inhibitors; D036387:Ephrin-B1; D036388:Ephrin-B2; D008024:Ligands; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D020794:Receptor Protein-Tyrosine Kinases; D036224:Receptor, EphB4; D036081:Receptors, Eph Family; D019061:src-Family Kinases; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases; C516743:Ptpn13 protein, mouse