The mTOR protein kinase receives stimulatory signals from nutrients as well as Ras and phosphatidylinositol-3-OH kinase (PI(3)K) downstream from growth factors. Functioning as a critical growth-control node, mTOR is the 'mammalian target of rapamycin', a fungal derivative that halts protein synthesis by complexing with immunophilin FK-506 binding protein FKBP12 peptide prolyl cis/trans isomerase.
Phosphatidylinositide-3' (PI 3)-kinase participates in Kit-ligand (KL)-induced adhesion of bone marrow-derived mast cells (BMMCs) to fibronectin. The Kit receptor tyrosine kinase is a member of the PDGF receptor subfamily that mediates diverse responses including proliferation, survival, chemotaxis, migration, differentiation, and adhesion to extracellular matrix. PKCs play a dual role as both positive and negative regulators of Kit function by acting as downstream mediators in addition to participating in a negative feedback loop that down-regulates Kit receptor activity. PKC is activated by diacylgylcerol and by products of PI-3 kinase. Kit participates in the secretion of inflammatory mediators in connective tissue mast cells. Receptor-proximal PI 3-kinase activation and activation of a PKC isoform appear to have a role in Kit-mediated secretory enhancement, adhesion, and cytoskeletal reorganization.[r]
Agonist stimulation of phosphatidylinositide 3-kinase (PI 3-kinase) activates a pathway that leads to activation of ADP-ribosylation factor (ARF) 6, which regulates plasma membrane trafficking and cortical actin formation by cycling between inactive GDP and active GTP-bound conformations.
Components of the Ras and PI(3)K signalling pathways are mutated in most human cancers. The high frequency of mutations in these pathways suggests that the loss of growth-control checkpoints and the promotion of cell survival in nutrient-limited conditions may be an obligate event in carcinogenesis.[r]