ng interests exist. been investigated. Until about two decades ago, cadherins were the only known critical cell– cell adhesion molecule for cell–cell adhesion, and 169939-93-9 web growth factor receptors and integrins were shown to be involved in cell movement and proliferation by cooperatively regulating the intracellular signals, including the small G proteins Rho and Ras, respectively. Although cadherins, growth factor receptors, and integrins were known to contribute to contact inhibition, these molecules could not completely account for its mechanisms. Our understanding of contact inhibition has progressed since the discovery of novel pathways, including the Hippo, merlin, and Eph-ephrin signaling pathways. Cadherins, through catenins, most likely regulate merlin, a product of the tumor suppressor gene merlin/Nf2, and merlin subsequently activates the Hippo pathway, which inhibits 
cell proliferation by inactivating the transcriptional coactivator YAP. Eph–ephrin trans-interactions initiate bidirectional signaling within the receptor- and ligand-expressing cells. Activation of the EphA receptor by trans-interacting with ephrin in neighbouring prostate cancer cells causes the retraction of their movement. We have shown that another family of CAMs nectins, consisting of four members, regulate cell–cell adhesion, cell movement, and cell proliferation in various types of cells. In epithelial cells, the trans-interactions of nectins induce the initial cell–cell adhesion, and then recruit cadherins to the nectin-based adhesion sites, eventually establishing adherens junctions . During or after AJ formation, nectins PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19769484 initially recruit junctional adhesion molecules to the adhesion sites, followed by the recruitment of occludin and claudins to the apical side of AJs in cooperation with cadherins, establishing tight junctions . Thus, cell–cell adhesion progresses in multiple stages. We have identified nectinlike molecule-5, a member of the Necl family of proteins consisting of five members, as the third regulatory factor for cell movement and proliferation, in addition to growth factor receptors and integrins. Necl-5 forms a complex with PDGF receptor and integrin V3, and is localized at the leading edges of migrating NIH3T3 cells in response to PDGF. This complex regulates dynamic activation and inactivation of the small G proteins Rap1, Rac, and RhoA, thereby inducing the formation of leading edge structures, such as lamellipodia, peripheral ruffles, and focal complexes, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19769777 required for cell migration. This complex also enhances cell proliferation by inhibiting sprouty2, a negative regulator of the Ras –extracellular signal-regulated kinase pathway. When two cultured NIH3T3 cells collide, Necl-5 at the leading edges trans-interacts with nectin-3 on the surface of the adjacent cells. Necl-5 is down-regulated from the cell surface by endocytosis, and the nectin-3 retained on the cell membrane trans-interacts with nectin-1, initiating cell–cell adhesion and subsequently recruiting cadherins to form AJs. Thus, nectins and Necl-5 cooperatively regulate cell–cell adhesion, cell movement, and cell proliferation, and play a role at the initiation stage of contact inhibition of cell movement and proliferation. Although contact inhibition has not been shown to occur at multiple stages, accumulating evidence suggests that contact inhibition is divided into at least two stages: the initiation stage with a decrease in cell movement and proliferation; and the maint
