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 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.
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Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Buxbaum
J D
JD
Peschon
J J
JJ
Corfas
G
G
D016475:3T3 Cells; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D002999:Clone Cells; D003001:Cloning, Molecular; D005576:Colforsin / Q000494:pharmacology; D019483:Disintegrins / Q000378:metabolism; D029721:Drosophila Proteins; D066246:ErbB Receptors / Q000378:metabolism*; D007700:Kinetics; D008387:Marine Toxins; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D019483:Disintegrins; D029721:Drosophila Proteins; D008387:Marine Toxins; D010080:Oxazoles; D020033:Protein Isoforms; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C076715:pervanadate; D005576:Colforsin; D019319:Okadaic Acid; D014638:Vanadates; D019284:Thapsigargin; C059041:calyculin A; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D051722:ADAM Proteins; C100953:KUZ protein, Drosophila; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D013755:Tetradecanoylphorbol Acetate