Integration of growth factor and nutrient signaling: implications for cancer biology.
Signaling networks that promote cell growth are frequently dysregulated in cancer. One regulatory network, which converges on effectors such as 4EBP1 and S6K1, leads to growth by promoting protein synthesis. Here, we discuss how this network is regulated by both extracellular signals, such as growth factors, and intracellular signals, such as nutrients. We discuss how mutations amplifying either type of signal can lead to tumor formation. In particular, we focus on the recent discovery that a tumor suppressor complex whose function is lost in tuberous sclerosis patients regulates the nutrient signal carried by the critical signaling protein TOR to the effectors 4EBP1 and S6K1. Finally, we describe how the small molecule rapamycin, which inhibits TOR and thereby the activation of these effectors, could be useful to treat tumors that have become dependent upon this pathway for growth.
Shamji
Alykhan F
AF
Harvard Biophysics Program, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Nghiem
Paul
P
Schreiber
Stuart L
SL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry; D018797:Cell Cycle Proteins; D002455:Cell Division; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D006133:Growth Substances; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; C087000:EIF4EBP1 protein, human; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1