fig 4.Three major signaling pathways that regulate cell size in normal cells. (A) The PI3K/AKT/mTOR pathway. An increase in cell number and cell size both can lead to organ growth. Cell number is dependent on the intricate balance between cell proliferation, which is controlled by extracellular mitogens and inhibitory molecules, and cell death, which is initiated in response to developmental cues or lack of survival factors. Cell size is dependent on cell growth, which is controlled by a balance between protein synthesis and protein degradation based on extracellular growth factors and nutrient sufficiency. Central to the regulation of cell growth is the mTOR pathway. The core components of the mTOR pathway are shown. (B) The c-Myc pathway. The Ras/PI3K/ERK pathway induces c-Myc. Myc mainly functions as a transcription factor to regulate target genes including those involved in cell cycle, apoptosis, cell metabolism and protein and RNA biosynthesis. Myc is also frequently upregulated in cancer cells due to genomic amplification (not shown). (C) The Hippo pathway. The pathway is thought to sense cell density and to regulate gene expression for control of organ size. The key downstream effector of the mammalian Hippo pathway is the Yes-associated protein (YAP), which function as a transcription co-activator. Mst is a mammalian homolog of Drosophila Hippo and encodes a kinase that phosphorylates Lats with cooperation from Sav. Phosphorylated Lats then exerts kinase activity on YAP. Phosphorylated YAP is then trapped in the cytoplasm by a 14-3-3 protein, until de-phosphorylation by a phosphatase such as PP1A allows translocation to the nucleus, thereby facilitating transcriptional regulation.