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J. Cell Biol.,
Volume 139, Number 4, November 17, 1997 995-1003
Department of Biochemistry and Department of Medicine, Vanderbilt University School of Medicine, Nashville,
Tennessee 37232-0146
The heregulin receptor tyrosine kinase
ErbB-4 is constitutively cleaved, in the presence or absence of ligand, by an exofacial proteolytic activity producing a membrane-anchored cytoplasmic domain
fragment of 80 kD. Based on selective sensitivity to inhibitors, the proteolytic activity is identified as that of a
metalloprotease. The 80-kD product is tyrosine phosphorylated and retains tyrosine kinase activity. Importantly, the levels of this fragment are controlled by proteasome function. When proteasome activity is inhibited for 6 h, the kinase-active 80-kD ErbB-4 fragment accumulates to a level equivalent to 60% of the
initial amount of native ErbB-4 (~106 receptors per
cell). Hence, proteasome activity is essential to prevent
the accumulation of a significant level of ligand-independent, active ErbB-4 tyrosine kinase generated by
metalloprotease activity. Proteasome activity, however,
does not act on the native ErbB-4 receptor before the
metalloprotease-mediated cleavage, as no ErbB-4 fragments accumulate when metalloprotease activity is
blocked. Although no ubiquitination of the native
ErbB-4 is detected, the 80-kD fragment is polyubiquitinated. The data, therefore, describe a unique pathway
for the processing of growth factor receptors, which involves the sequential function of an exofacial metalloprotease and the cytoplasmic proteasome.
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