Receptor tyrosine kinases bind with ligand and initiate the signaling pathway via intermediate molecules (IRS). PI3K becomes activated, which results in phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP₂) to phosphatidylinositol 3,4,5-trisphosphate (PIP₃), a process that is reversed by PTEN. At the cell membrane, proteins with pleckstrin homology domains then become phosphorylated via PIP₃ (phosphoinositide-dependent protein kinase–1 [PDK1] and AKT). PDK1 can also phosphorylate critical residues on AKT. The tumor suppressor complex of TSC1/TSC2 normally inhibits mTOR activation via Ras homolog enriched in brain (Rheb). Activated AKT prevents this inhibition, leading to activation of the mTOR/Raptor complex known as mTOR complex 1 (mTORC1). This complex can be inhibited by rapamycin and its analogs, including everolimus. Ultimately, mTORC1 leads to the activation of downstream proteins involved in the initiation of protein synthesis, resulting in cellular growth. Receptor tyrosine kinase activation also initiates MAPK pathway signaling, which leads to cell cycle progression and proliferation. MAPK pathway activation can also augment PI3K signaling. MEK, MAPK/ERK kinase.