Accession Number : ADB281601


Title :   Engineering of Specific Tissue Inhibitors to Block ADAM Type Metalloprotease-Mediated Mammary Neoplasia


Descriptive Note : Annual summary rept. 1 Jul 1998-30 Jun 2001


Corporate Author : CALIFORNIA UNIV SAN FRANCISCO


Personal Author(s) : Yan, Yibing ; Werb, Zena


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/b281601.pdf


Report Date : Jul 2001


Pagination or Media Count : 33


Abstract : Communication between different signaling pathways enables cells to coordinate the responses to diverse environmental signals. Activation of the transmembrane growth factor precursor plays a critical role in this communication and often involves in metalloproteases-mediated proteolysis. Stimulation of G protein-coupled receptors (GPCR) transactivates the epidermal growth factor receptors (EGFR), which occurs via a metalloprotease-dependent cleavage of heparin-binding epidermal growth factor (HB-ECF). However, the metalloprotease mediating the transactivation remains elusive. We show that the integral membrane metalloprotease Kuzbanian (KUZ, ADAM10), which controls Notch signaling by cleaving Notch and its ligand Delta in Drosophila, stimulates GPCR transactivation of EGFR. Upon stimulation of the bombesin receptors, KUZ increases the docking and activation of adaptors SHC and Gabl on the EGFR, and activation of Ras and Erk. In contrast, transfection of a protease-domain deleted KUZ (K.MP) 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 GPCR and EGFR signaling pathways.


Descriptors :   *EPITHELIUM , *GENES , *MAMMARY GLANDS , *PROTEINS(CONJUGATED) , *BREAST CANCER , ACTIVATION , TISSUES(BIOLOGY) , MAMMALS , NEOPLASMS , MUTATIONS , LIGANDS , CYTOPLASM , MICE , INHIBITORS , LIFE SPAN(BIOLOGY) , INHIBITION , DEATH , CELLS(BIOLOGY) , RECEPTOR SITES(PHYSIOLOGY) , EPIDERMIS , GROWTH(PHYSIOLOGY) , HEPARIN , DROSOPHILA


Subject Categories : Genetic Engineering and Molecular Biology
      Anatomy and Physiology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE