A Conserved Role of IQGAP1 in Regulating TOR Complex 1 Article (Web of Science)


  • Defining the mechanisms that orchestrate cell growth and division is crucial to understanding cell homeostasis, which impacts human diseases like cancer and diabetes. IQGAP1, a widely conserved effector/regulator of the GTPase CDC42 is a putative oncogene that control cell proliferation, however, its mechanism in tumorigenesis is unknown. The mTOR pathway, the center of cell growth control, is commonly activated in human cancers, but proved ineffective as clinical target due to incomplete understanding of its mechanisms in cell growth inhibition. Using complementary studies in yeast and mammalian cells, here we report a potential role for IQGAP1 in regulating the negative feedback loop (NFL) of the target of rapamycin complex1 (mTORC1) that control cell growth. Two-hybrid screens identified yeast TORC1-specific subunit, Tco89p, as an Iqg1p-binding partner sharing roles in rapamycin-sensitive growth, axial bud-site selection and cytokinesis, thus coupling cell growth and division. Mammalian IQGAP1 binds mTORC1 and Akt1 and in response to epidermal growth factor (EGF), cells expressing the mTORC1/Akt1-binding region, IQGAP1IR-WW, contained attenuated pERK1/2 activity and inactive glycogen synthase kinase 3α/β (pGSK3α/β), which control apoptosis. Interestingly, these cells displayed high level of pAkt1S473, but attenuated level of the mTORC1-dependent kinase, pS6k1T389 and induced mTORC1/Akt1- and EGF-dependent transformed phenotypes. Moreover, IQGAP1 appears to influence cell abscission and its activity is elevated in carcinoma cell lines. These findings support the hypothesis that IQGAP1 acts upstream on the mTORC1/S6K1→Akt1 NFL and downstream of it to couple cell growth and division and thus like a rheostat regulates cell homeostasis, dysregulation of which leads to tumorigenesis or other diseases. These results could have implications on developing the next generation of anticancer therapeutics.


publication date

  • 2012

published in