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.