The mTOR signaling network: insights from its role during embryonic development.
Target of Rapamycin (TOR) signaling, originally discovered as the pathway affected by an antifungal macrolide, exemplifies the potential of medicinal chemistry as a discovery tool. Three decades from its identification, signaling involving the TOR kinase has evolved into a complex network with a crucial role in vertebrate growth control. Specifically, it integrates signals to coordinate cell growth (i.e., enhanced mass and size) and cell cycle progression with sufficiency of nutrients, energy, and growth factors. In this review, we discuss multiple aspects of TOR signaling, including cellular regulators and mediators, human diseases related to TOR dysregulation such as cancer, and signaling nodes in the pathway amenable to targeted drug inhibition. The functions and mechanisms of TOR during embryonic development highlight the dynamic role of TOR signaling and reveal additional functions beyond cell growth control. Embryonic TOR signaling has differential tissue-specific and temporal effects, and is involved in organogenesis, sexual differentiation, and epithelial-to-mesenchymal transition signaling. Molecular mechanisms that may contribute to embryonic-specific TOR functions are also examined here. Finally, this review discusses the complex signaling of mTOR in cancer and the development of mTOR inhibitors for cancer therapy.
Hwang
M
M
Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Perez
C A
CA
Moretti
L
L
Lu
B
B
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation; D047108:Embryonic Development / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D009928:Organ Specificity; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D020690:GTPase-Activating Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D019204:GTP-Binding Proteins; D020123:Sirolimus