Regulation of platelet-derived growth factor-induced Ras signaling by poliovirus receptor Necl-5 and negative growth regulator Sprouty2.
Necl-5, known as a poliovirus receptor and up-regulated in many cancer cells, enhances platelet-derived growth factor (PDGF)-induced activation of Ras-Raf-MEK-ERK signaling, but not PDGF-induced tyrosine phosphorylation of PDGF receptor, resulting in facilitation of cell proliferation. Here, we showed that Necl-5 interacted with Sprouty2, known to be a negative regulator of growth factor-induced signaling, and reduced the inhibitory effect of Sprouty2 on PDGF-induced Ras signaling. Necl-5 was reported to be down-regulated by its trans-interaction with nectin-3 upon cell-cell contact, initiating cooperative cell-cell adhesion with cadherin. This down-regulation of Necl-5 caused tyrosine phosphorylation of Sprouty2 by c-Src, which was activated by PDGF receptor in response to PDGF, and inhibited PDGF-induced Ras signaling. Thus, Necl-5 and Sprouty2 cooperatively regulate PDGF-induced Ras signaling. The roles of Necl-5 and Sprouty2 in contact inhibition for cell proliferation are also discussed.
Kajita
Mihoko
M
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita, Osaka 565-0871, Japan.
Ikeda
Wataru
W
Tamaru
Yoshiyuki
Y
Takai
Yoshimi
Y
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000077214:Becaplermin; D000081247:CSK Tyrosine-Protein Kinase; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism*; D019061:src-Family Kinases
D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011991:Receptors, Virus; D011994:Recombinant Proteins; C476587:Taa1 protein, mouse; C066100:poliovirus receptor; D000077214:Becaplermin; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; D018631:ras Proteins