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© The Rockefeller University Press, 0021-9525/1997//995 $5.00
The Journal of Cell Biology, Volume 139, Number 4, , 1997 995-1003

Article

Constitutive Proteolysis of the ErbB-4 Receptor Tyrosine Kinase by a Unique, Sequential Mechanism



Manuela Vecchi and Graham Carpenter

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.

Abbreviations used in this paper: ECL, enhanced chemiluminescence; PLC-{gamma}1, phospholipase c-{gamma}1; WG, wheat germ.

This research was supported by a National Cancer Institute grant (CA24071).

Manuela Vecchi's current address is European Institute of Oncology, Via Ripamonte 435, 20141 Milan, Italy.

Address all correspondence to Graham Carpenter, Department of Biochemistry, 647 Light Hall, Vanderbilt University School of Medicine, Nashville, TN 37232-0146. Tel.: (615) 322-6678. Fax: (615) 322-2931.


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