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

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-␣-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.The HER4/erbB4 receptor tyrosine kinase is a member of the EGF 1 receptor family, which also includes the EGF receptor (HER1 or erbB1), HER2 (erbB2 or Neu), and HER3 (erbB3) (1-4). HER4 is a receptor for the neuregulins (NRGs) (5), a family of growth and differentiation factors that includes NRG (also known as acetylcholine receptor-inducing activity (6), glial growth factor (7), heregulin (8), and neu differentiation factor (9)), NRG2 (10 -12), NRG3 (13), and NRG4 (14). HER4 can also bind and be activated by heparin-binding EGF growth factor (15), betacellulin (16), and epiregulin (17), members of the EGF family which, unlike the NRGs, are also ligands for the EGF receptor. HER4 mRNA is expressed in several tissues such as heart, brain, kidney, and skeletal muscle (2), suggesting that this receptor is involved in the development and maintenance of a variety of organs and cell types. In fact, HER4 is essential for heart development: HER4-deficient mice die as embryos due to the lack of myocardial trabeculae (18). HER4 knockout mice also manifest neural defects, indicating that its function is critical for nervous system development as well. HER4 has also been implicated in the pathogenesis of different types of cancer (2,19,20). Thus, it is likely that the control of expression and function of HER4 is important in normal development as well as in disease.In an earlier study, we reported the identification of a novel isoform of HER4 (HER4 JM-b) that differs from the original receptor (HER4 JM-a) in the juxtamembrane portion of the extracellular domain of the receptor. The juxtamembrane region of HER4 JM-b contains a stretch of 13 amino acids that replaces a stretch of 23 amino acids present in HER4 JM-a. The two receptor isoforms differ in their tissue distribution. The two isoforms also vary in their response to phorbol ester stimulation, which leads to a rapid down-regulation of surface express...

Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms

“…These findings imply that mAb 1479 may interfere with ErbB4 cleavage by a mechanism similar to that of trastuzumab. Whether the mechanism involves blocking an interaction of ErbB4 with the ErbB4-cleaving enzyme TACE that cleaves the receptor at the JM-a-specific domain (Elenius et al, 1997;Rio et al, 2000;Cheng et al, 2003) is currently not known. mAb 1479 also efficiently stimulated downregulation of total cellular ErbB4 protein levels.…”

“…Two of the isoforms differ in the intracellular cytoplasmic domain (isoforms CYT-1 and CYT-2) and two in the extracellular juxtamembrane region (isoforms JM-a and JM-b) of ErbB4. The extracellular isoform JM-a can be cleaved by tumor necrosis factor-a-converting enzyme (TACE) (Rio et al, 2000) whereas the JM-b isoform is proteinase resistant (Elenius et al, 1997). Cleavage by TACE triggers a second cleavage of ErbB4 involving g-secretase activity (Lee et al, 2002).…”

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

“…Expression vectors for the JMa splice variants of ERBB4 has been described previously. 32 All ERBB4 constructs were of the cyt1 30 splice variant.…”

Differential expression of neuregulins and their receptors in the olfactory bulb layers of the developing mouse

“…In ST14A cells stably transfected with the full-length ErbB4-JMa, it shows a 180 kDa full-length ErbB4 and a 85 kDa ∼ band (Fig. 4A), likely corresponding to the cytoplasmic fragment derived from the cleavage of ErbB4-JMa by tumor necrosis factor-alpha-converting enzyme (TACE; Rio et al, 2000). ST14A cells stably transfected with ErbB4-JMb or vector alone did not show this 85 kDa band.…”