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

Yibing Yan, Kyoko Shirakabe, Zena Werb

Research output: Contribution to journalArticle

268 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)221-226
Number of pages6
JournalJournal of Cell Biology
Volume158
Issue number2
Publication statusPublished - 2002 Jul 22

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Metalloproteases
G-Protein-Coupled Receptors
Epidermal Growth Factor Receptor
Transcriptional Activation
Epidermal Growth Factor
Heparin
Bombesin Receptors
Morpholinos
src Homology Domains
Antisense Oligonucleotides
Proteolysis
Transfection
Intercellular Signaling Peptides and Proteins
Peptide Hydrolases
ErbB Receptors
Membranes
Proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this

The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors. / Yan, Yibing; Shirakabe, Kyoko; Werb, Zena.

In: Journal of Cell Biology, Vol. 158, No. 2, 22.07.2002, p. 221-226.

Research output: Contribution to journalArticle

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