Ectodysplasin A (EDA) Signaling: From Skin Appendage to Multiple Diseases

Abstract

Ectodysplasin A (EDA) signaling is initially identified as morphogenic signaling regulating the formation of skin appendages including teeth, hair follicles, exocrine glands in mammals, feathers in birds and scales in fish. Gene mutation in EDA signaling causes hypohidrotic ectodermal dysplasia (HED), a congenital hereditary disease with malformation of skin appendages. Interestingly, emerging evidence suggests that EDA and its receptors can modulate the proliferation, apoptosis, differentiation and migration of cancer cells, and thus may regulate tumorigenesis and cancer progression. More recently, as a newly discovered hepatocyte factor, EDA pathway has been demonstrated to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and type II diabetes by regulating glucose and lipid metabolism. In this review, we summarize the function of EDA signaling from skin appendage development to multiple other diseases, and discuss the clinical application of recombinant EDA protein as well as other potential targets for disease intervention.

Keywords: EDA signaling; HED; NAFLD; cancer; skin appendage.

Figure 1

Schematic drawing of the signaling transduction of EDA pathway. Secreted EDA binds to its receptor EDAR and forms a complex with the intracellular EDARADD, then recruits TAK1, TAB2, and TRAF6, induces IKK phosphorylation, and translocates NF-κB into the nucleus, followed by attaching with the BAF complex, and eventually facilitates specific gene transcription (*: gene mutations identified in HED patients).

Figure 2

The EDA pathway involved in the pathogenesis of HED, cancer, and NAFLD. Gene mutations in the EDA pathway lead to hypohidrotic ectodermal dysplasia (HED), with clinical symptoms including xerophthalmia, sweat gland dysplasia, hypodontia, and follicular dysplasia. EDA signaling is also involved in tumorigenesis and cancer progression of breast cancer, colorectal cancer, oral cancer, and melanoma. In addition, EDA, as a newly discovered hepatocyte factor, may be highly involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD).