ADAM17 is essential for ectodomain shedding of the EGF-receptor ligand amphiregulin.

Authors

Vishnu Hosur, The Jackson LaboratoryFollow
Michelle L Farley, The Jackson LaboratoryFollow
Lisa M. Burzenski, The Jackson LaboratoryFollow
Leonard D. Shultz, The Jackson LaboratoryFollow
Michael V. Wiles, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

2018

JAX Source

FEBS Open Bio 2018; 8(4):702-710

Volume

8

Issue

4

First Page

702

Last Page

710

ISSN

2211-5463

PMID

29632822

DOI

https://doi.org/10.1002/2211-5463.12407

Grant

CA034196, Director's Innovation Fund at The Jackson Laboratory

Abstract

The epidermal growth factor (EGF)-receptor ligand amphiregulin (AREG) is a potent growth factor implicated in proliferative skin diseases and in primary and metastatic epithelial cancers. AREG, synthesized as a propeptide, requires conversion to an active peptide by metalloproteases by a process known as ectodomain shedding. Although (ADAM17) a disintegrin and metalloprotease 17 is a key sheddase of AREG, ADAM8-, ADAM15-, and batimastat (broad metalloprotease inhibitor)-sensitive metalloproteases have also been implicated in AREG shedding. In the present study, using a curly bare (Rhbdf2^cub ) mouse model that shows loss-of-hair, enlarged sebaceous gland, and rapid cutaneous wound-healing phenotypes mediated by enhanced Areg mRNA and protein levels, we sought to identify the principal ectodomain sheddase of AREG. To this end, we generated Rhbdf2^cub mice lacking ADAM17 specifically in the skin and examined the above phenotypes of Rhbdf2^cub mice. We find that ADAM17 deficiency in the skin of Rhbdf2^cub mice restores a full hair coat, prevents sebaceous gland enlargement, and impairs the rapid wound-healing phenotype observed in Rhbdf2^cub mice. Furthermore, in vitro, stimulated shedding of AREG is abolished in Rhbdf2^cub mouse embryonic keratinocytes lacking ADAM17. Thus, our data support previous findings demonstrating that ADAM17 is the major ectodomain sheddase of AREG. FEBS Open Bio 2018; 8(4):702-710.

Comments

We are grateful to Stephen B. Sampson for critical reading and for providing valuable comments on the manuscript. We also thank Scientific Services at The Jackson Laboratory for assistance with histology (Elaine Bechtel) and flow cytometry (Will Schott and Ted Duffy).

Open access under the terms of the Creative Commons Attribution License.

Recommended Citation

Hosur V, Farley M, Burzenski LM, Shultz LD, Wiles MV. ADAM17 is essential for ectodomain shedding of the EGF-receptor ligand amphiregulin. FEBS Open Bio 2018; 8(4):702-710