A schematic model of intracellular signal components that control S-phase entry in vestibular epithelia from neonatal mammals. Inhibitors and activators that were used to identify the elements in the signaling cascades are shown inboxes. Binding of GGF2 and other growth factors (GF) to receptor tyrosine kinases (RTK, ErbB2) leads to activation in both the PI-3K cascade and the MAPK cascade. Activated ERK–MAPKs can translocate to the nucleus, resulting in changes in gene expression. Active PI-3K leads to the production of PI-3,4-P2 and PI-3,4,5-P3, which can activate PKCs and Akt–PKB. Certain activated isoforms of PKC and Akt–PKB phosphorylate and activate mTOR, which leads to the activation of p70/85 S6Ks. When p70 S6K is active, it phosphorylates and activates the S6 ribosomal protein, which is required for the synthesis of proteins involved in S-phase entry. Activated p85 S6K is translocated to the nucleus and mediates cell-cycle progression. Phospholipase C (PLC) induces the production of DAG and IP₃. DAG can activate certain PKCs, which can activate the MAPK pathway. The production of IP₃ increases the release of intracellular calcium ([Ca²⁺]_i), which can also lead to the activation of PKCs. The anchorage-dependent proliferative response depends on the level of signals from growth factor receptors as well as anchorage of the cell to the extracellular matrix (ECM) via integrins. Bindings of integrins to specific components of the ECM can lead to the activation of the PI-3K cascade and the MAPK cascade.GGF2, Glial growth factor; ErbB2, receptor tyrosine kinase of the ErbB family; MEK, mitogen-activated protein kinase kinase; p70 S6K, the 70 kDa S6 protein kinase; p85 S6K, the 85 kDa S6 protein kinase; Akt–PKB, protein kinase B.