Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism*
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Becaplermin
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CSK Tyrosine-Protein Kinase
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism*
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Down-Regulation
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Humans
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Intracellular Signaling Peptides and Proteins
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MAP Kinase Signaling System
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Models, Biological
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NIH 3T3 Cells
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Phosphorylation
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Platelet-Derived Growth Factor / pharmacology*
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Protein Serine-Threonine Kinases
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-sis
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Receptors, Platelet-Derived Growth Factor / metabolism
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Receptors, Virus / genetics
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Receptors, Virus / metabolism*
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Recombinant Proteins / pharmacology
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Signal Transduction / drug effects
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ras Proteins / metabolism*
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src-Family Kinases
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Neoplasm
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Cell Adhesion Molecules
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Neoplasm Proteins
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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Receptors, Virus
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Recombinant Proteins
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Taa1 protein, mouse
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poliovirus receptor
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Becaplermin
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Protein-Tyrosine Kinases
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Receptors, Platelet-Derived Growth Factor
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human
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Protein Serine-Threonine Kinases
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Spry2 protein, mouse
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ras Proteins