Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains.
A yeast two-hybrid analysis has shown that the juxtamembrane region of FGF receptor 3 (FGFR3) interacts with the cytoplasmic domain of EphA4, which is a member of the largest family of receptor tyrosine kinases. Complex formation between the two receptors was shown to be mediated by direct interactions between the juxtamembrane domain of FGFR1, FGFR2, FGFR3, or FGFR4 and the N-terminal portion of the tyrosine kinase domain of EphA4. Activation of FGFR1 in transfected cells resulted in tyrosine phosphorylation of a kinase-negative EphA4 mutant and activation of EphA4 led to tyrosine phosphorylation of a kinase-negative FGFR1 mutant. Moreover, both receptors stimulate tyrosine phosphorylation of the docking protein FRS2alpha and induce mitogen-activated protein kinase stimulation with a time course and intensity that depends on the ligand that is applied. We also demonstrate that FGF-receptor-mediated mitogen-activated protein kinase stimulation is potentiated in cells costimulated with ephrin-A1. The direct interaction between EphA4 and FGFRs and the potentiation of FGF response that is induced by ephrin-A1 stimulation may modulate the biological responses that are mediated by these receptor families in cells or tissues in which the two receptors are coexpressed.
Yokote
Hideyuki
H
Department of Molecular Cell Biology, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
Fujita
Koji
K
Jing
Xuefeng
X
Sawada
Takahiro
T
Liang
Sitai
S
Yao
Li
L
Yan
Xiaomei
X
Zhang
Yueqiang
Y
Schlessinger
Joseph
J
Sakaguchi
Kazushige
K
D000911:Antibodies, Monoclonal / Q000737:chemistry; D002454:Cell Differentiation; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D036382:Ephrin-A1 / Q000737:chemistry; D017353:Gene Deletion; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D036122:Receptor, EphA4 / Q000235:genetics* / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques; D014443:Tyrosine / Q000737:chemistry
D000911:Antibodies, Monoclonal; D036382:Ephrin-A1; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D036122:Receptor, EphA4