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Published online 15 July 2002. doi:10.1083/jcb.200112026
 The Rockefeller University Press, 0021-9525 $8.00
The Journal of Cell Biology
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© The Rockefeller University Press, 0021-9525
The Journal of Cell Biology

Article

 The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein–coupled receptors

Yibing Yan, Kyoko Shirakabe and Zena Werb

Department of Anatomy, University of California, San Francisco, CA 94143

Address correspondence to Zena Werb, Department of Anatomy, HSW 1321, University of California, 513 Parnassus Ave., San Francisco, CA 94143-0452. Tel.: (415) 476-4622. Fax: (415) 476-4565. E-mail: zena{at}itsa.ucsf.edu

Communication between different signaling pathways enables cells to coordinate the responses to diverse environmental signals. Activation of the transmembrane growth factor precursors plays a critical role in this communication and often involves metalloprotease-mediated proteolysis. Stimulation of G protein–coupled receptors (GPCR) transactivates the EGF receptors (EGFRs), which occurs via a metalloprotease-dependent cleavage of heparin-binding EGF (HB-EGF). However, the metalloprotease mediating the transactivation remains elusive. We show that the integral membrane metalloprotease Kuzbanian (KUZ; ADAM10), which controls Notch signaling in Drosophila, stimulates GPCR transactivation of EGFR. Upon stimulation of the bombesin receptors, KUZ increases the docking and activation of adaptors Src homology 2 domain–containing protein and Gab1 on the EGFR, and activation of Ras and Erk. In contrast, transfection of a protease domain–deleted KUZ, or blocking endogenous KUZ by morpholino antisense oligonucleotides, suppresses the transactivation. The effect of KUZ on shedding of HB-EGF and consequent transactivation of the EGFR depends on its metalloprotease activity. GPCR activation enhances the association of KUZ and its substrate HB-EGF with tetraspanin CD9. Thus, KUZ regulates the relay between the GPCR and EGFR signaling pathways.

Key Words: signal crosstalk; bombesin; HB-EGF; shedding; tetraspanin


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