Silencing of ErbB3/ErbB2 signaling by immunoglobulin-like Necl-2.
ErbB2 and ErbB3, members of the EGF receptor/ErbB family, form a heterodimer upon binding of a ligand, inducing the activation of Rac small G protein and Akt protein kinase for cell movement and survival, respectively. The enhanced ErbB3/ErbB2 signaling causes tumorigenesis, invasion, and metastasis. We found here that the ErbB3/ErbB2 signaling is regulated by immunoglobulin-like Necl-2, which is down-regulated in various cancer cells and serves as a tumor suppressor. The extracellular region of ErbB3, but not ErbB2, interacted in cis with that of Necl-2. This interaction reduced the ligand-induced, ErbB2-catalyzed tyrosine phosphorylation of ErbB3 and inhibited the consequent ErbB3-mediated activation of Rac and Akt, resulting in the inhibition of cancer cell movement and survival. These inhibitory effects of Necl-2 were mediated by the protein-tyrosine phosphatase PTPN13 which interacted with the cytoplasmic tail of Necl-2. We describe here this novel mechanism for silencing of the ErbB3/ErbB2 signaling by Necl-2.
Kawano
Satoshi
S
Division of Molecular and Cellular Biology, Department of Biochemistry, Kobe University Graduate School of Medicine, Kobe 650-0017, Hyogo, Japan.
Ikeda
Wataru
W
Kishimoto
Megumi
M
Ogita
Hisakazu
H
Takai
Yoshimi
Y
D000818:Animals; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D002460:Cell Line; D019281:Dimerization; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C498598:Cadm1 protein, mouse; C524056:Erbb2 protein, mouse