Tumor Necrosis Factor-α-converting Enzyme Is Required for Cleavage of erbB4/HER4

Carlos Rio,Joseph D Buxbaum,Jacques J Peschon,Gabriel Corfas

doi:10.1074/jbc.275.14.10379

Abstract

HER4 is a member of the epidermal growth factor receptor family and has an essential function in heart and neural development. Identification of two HER4 isoforms, HER4 JM-a and JM-b, which differ in their extracellular juxtamembrane region and in their susceptibility to cleavage after phorbol ester stimulation, showed that the juxtamembrane region of the receptor is critical for proteolysis. We now demonstrate that phorbol ester and pervanadate are effective stimuli for HER4 JM-a processing and that the HER4 JM-b isoform does not undergo cleavage in response to any of the stimuli studied. We also show that HER4 JM-a is not cleaved in cells lacking the metalloprotease tumor necrosis factor-alpha-converting enzyme (TACE) and that reexpression of TACE in these cells restores constitutive and regulated processing of HER4 JM-a. Moreover, we show that the sequence specific to the HER4 JM-a juxtamembrane region is sufficient to confer susceptibility to phorbol 12-myristate 13-acetate-induced cleavage of the HER2 receptor. In conclusion, we provide evidence that TACE is essential for the regulated shedding of the HER4 JM-a receptor.

Highlights

HER4 is a member of the epidermal growth factor receptor family and has an essential function in heart and neural development
Phorbol Ester and Pervanadate Induce Cleavage of HER4 JM-a but not of HER4 JM-b—Previous studies showed that the HER4 receptor is endocytosis-impaired [33] but that the level of receptor surface expression can be regulated by receptor shedding, which can be induced by phorbol ester [22] and pervanadate [44]
With the identification of different juxtamembrane isoforms of HER4, we demonstrated that phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC), led to a reduction of radioactive NRG␤1 binding in cells expressing the JM-a but not the JM-b isoform [21]

Summary

Introduction

HER4 is a member of the epidermal growth factor receptor family and has an essential function in heart and neural development. We first used this assay to confirm our observation on the differences between the response of the two HER4 isoforms to PMA stimulation, using NIH 3T3 cell lines that express similar levels of the HER4 isoforms (Ref. 21; see Fig. 1B).

Results

Conclusion