The TSC/Rheb/mTOR signaling pathway plays important roles in protein synthesis, growth and cell cycle progression in response to nutrients, energy and growth factors such as insulin and insulin like growth factor. Overactivation of this signaling pathway is detected in a variety of human cancers and rapamycin, an inhibitor of mTOR, is being evaluated in clinical trials. Our recent work demonstrated that a single amino acid change can confer constitutive activation. More recently, we have made an important discovery that activating mutants of mTOR can be identified in human cancer genome database. In this application, we will focus on these mTOR mutants and ask first whether these mutants exhibit transforming activities. We will then carry out experiments aimed at gaining insight into the mechanism of activation of mTOR by the mutations. Finally, we will use fission yeast as a system amenable to genetic analysis to gain further insight into the mechanism of activation of the TOR signaling.
The mTOR signaling plays critical roles in growth and proliferation of mammalian cells. Deregulation of this signaling pathway causes cancer and genetic disorders. We will identify and characterize mutations in mTOR that confer constitutive activation.
|Heard, Jeffrey J; Phung, Ivy; Potes, Mark I et al. (2018) An oncogenic mutant of RHEB, RHEB Y35N, exhibits an altered interaction with BRAF resulting in cancer transformation. BMC Cancer 18:69|
|Lu, Jie; Yoshimura, Kohei; Goto, Koichi et al. (2015) Nanoformulation of Geranylgeranyltransferase-I Inhibitors for Cancer Therapy: Liposomal Encapsulation and pH-Dependent Delivery to Cancer Cells. PLoS One 10:e0137595|
|Mortazavi, Fariborz; Lu, Jie; Phan, Ryan et al. (2015) Significance of KRAS/PAK1/Crk pathway in non-small cell lung cancer oncogenesis. BMC Cancer 15:381|
|Chantaravisoot, Naphat; Wongkongkathep, Piriya; Loo, Joseph A et al. (2015) Significance of filamin A in mTORC2 function in glioblastoma. Mol Cancer 14:127|
|Sato, Tatsuhiro; Akasu, Hitomi; Shimono, Wataru et al. (2015) Rheb protein binds CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase) protein in a GTP- and effector domain-dependent manner and influences its cellular localization and carbamoyl-phosphate synthetase (CPSase) activity J Biol Chem 290:1096-105|
|Coffman, Kimberly; Yang, Bing; Lu, Jie et al. (2014) Characterization of the Raptor/4E-BP1 interaction by chemical cross-linking coupled with mass spectrometry analysis. J Biol Chem 289:4723-34|
|Heard, Jeffrey J; Fong, Valerie; Bathaie, S Zahra et al. (2014) Recent progress in the study of the Rheb family GTPases. Cell Signal 26:1950-7|
|Zimonjic, Drazen B; Chan, Lai N; Tripathi, Veenu et al. (2013) In vitro and in vivo effects of geranylgeranyltransferase I inhibitor P61A6 on non-small cell lung cancer cells. BMC Cancer 13:198|
|Tamanoi, Fuyuhiko; Lu, Jie (2013) Recent progress in developing small molecule inhibitors designed to interfere with ras membrane association: toward inhibiting K-Ras and N-Ras functions. Enzymes 34 Pt. B:181-200|
|Akhavan, David; Pourzia, Alexandra L; Nourian, Alex A et al. (2013) De-repression of PDGFR? transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients. Cancer Discov 3:534-47|
Showing the most recent 10 out of 95 publications