Furthermore, it has been shown that cell-cell adhesion formation not only restricts growth and proliferation by imposing physical constraints such as cell area, but also by triggering signaling pathways that downregulate proliferation. One such pathway is the Hippo-YAP signaling pathway, which is largely responsible for inhibiting cell growth in mammals. This pathway consists primarily of a phosphorylation cascade involving serine kinases and is mediated by regulatory proteins, which regulate cell growth by binding to growth-controlling genes. The serine/threonine kinase Hippo (Mst1/Mst2 in mammals) activates a secondary kinase (Lats1/Lats2), which phosphorylates YAP, a transcriptional activator of growth genes. The phosphorylation of YAP serves to export it from the nucleus and prevent it from activating growth-promoting genes; this is how the Hippo-YAP pathway inhibits cell growth. More importantly, the Hippo-YAP pathway uses upstream elements to act in response to cell-cell contact and controls density-dependent inhibition of proliferation. For example, cadherins are transmembrane proteins that form cellular junctions via homophilic binding and thus act as detectors for cell-cell contact. Cadherin-mediated activation of the inhibitory pathway involves the transmembrane E-cadherin forming a homophilic bond in order to activate α- and β-catenin, which then stimulate downstream components of the Hippo-YAP pathway to ultimately downregulate cell growth. This is consistent with the finding that E-cadherin overexpression hinders metastasis and tumorigenesis. Because YAP is shown to be associated with mitogenic growth factor signaling and thus cell proliferation, it is likely that future studies will focus on the Hippo-YAP pathway's role in cancer cells.