Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4

HER4 is a member of the epidermal growth factor receptor family and has an essential function in heart and neural development. Identification of two H ER4 isoforms, HER4 JM-a and JM-b, which differ in their extracellular juxta membrane region and in their susceptibility to cleavage after phorbol ester stimulation, showed that the juxtamembrane region of the receptor is criti cal for proteolysis. We now demonstrate that phorbol ester and pervanadate are effective stimuli for HER4 JM-a processing and that the HER4 JM-b isofo rm 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 metalloproteas e tumor necrosis factor-alpha-converting enzyme (TACE) and that reexpressio n 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 ju xtamembrane region is sufficient to confer susceptibility to phorbol 12-myr istate 13-acetate-induced cleavage of the HERS receptor. In conclusion, we provide evidence that TACE is essential for the regulated shedding of the H ER4 JM-a receptor.