The ectodermal dysplasia receptor activates the nuclear factor-kappaB, JNK, and cell death pathways and binds to ectodysplasin A.
The ectodermal dysplasia receptor (EDAR) is a recently isolated member of the tumor necrosis factor receptor family that has been shown to play a key role in the process of ectodermal differentiation. We present evidence that EDAR is capable of activating the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways and that these activities are impaired in mutants lacking its death domain or those associated with anhidrotic ectodermal dysplasia and the downless phenotype. Although EDAR possesses a death domain, it did not interact with the death domain-containing adaptor proteins TRADD and FADD. EDAR successfully interacted with various TRAF family members; however, a dominant-negative mutant of TRAF2 was incapable of blocking EDAR-induced nuclear factor-kappaB or JNK activation. Collectively, the above results suggest that EDAR utilizes a novel signal transduction pathway. Finally, ectodysplasin A can physically interact with the extracellular domain of EDAR and thus represents its biological ligand.
Kumar
A
A
Hamon Center for Therapeutic Oncology Research and the Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas 75390-8593, USA.
Eby
M T
MT
Sinha
S
S
Jasmin
A
A
Chaudhary
P M
PM
D016923:Cell Death; D004476:Ectodermal Dysplasia; D053331:Ectodysplasins; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000097782:NF-kappaB-Inducing Kinase
D053331:Ectodysplasins; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor; D000097782:NF-kappaB-Inducing Kinase