Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction.
Transmembrane B ephrins and their Eph receptors signal bidirectionally. However, neither the cell biological effects nor signal transduction mechanisms of the reverse signal are well understood. We describe a cytoplasmic protein, PDZ-RGS3, which binds B ephrins through a PDZ domain, and has a regulator of heterotrimeric G protein signaling (RGS) domain. PDZ-RGS3 can mediate signaling from the ephrin-B cytoplasmic tail. SDF-1, a chemokine with a G protein-coupled receptor, or BDNF, act as chemoattractants for cerebellar granule cells, with SDF-1 action being selectively inhibited by soluble EphB receptor. This study reveals a pathway that links reverse signaling to cellular guidance, uncovers a novel mode of control for G proteins, and demonstrates a mechanism for selective regulation of responsiveness to neuronal guidance cues.
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Department of Cell Biology and Program in Neuroscience, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Sun
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Klein
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RS
Flanagan
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JG
D000818:Animals; D001681:Biological Assay; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology; D002630:Chemotactic Factors / Q000378:metabolism* / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D036387:Ephrin-B1; D036388:Ephrin-B2; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D020710:RGS Proteins; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D020798:Two-Hybrid System Techniques; D014981:Xenopus
D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C515256:Cxcl12 protein, mouse; D036387:Ephrin-B1; D036388:Ephrin-B2; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D020710:RGS Proteins; C415085:Rgs3 protein, mouse; D019204:GTP-Binding Proteins; D020962:Heterotrimeric GTP-Binding Proteins