Tianyan Gao

Bio / Education: 

B.S. Beijing Medical University, Beijing, China
Ph.D. Northwestern University, Chicago, IL
Postdoctoral fellow, University of California San Diego, La Jolla, CA.

Research Description: 

Precise control of the balance between protein phosphorylation and dephosphorylation is critical for living organisms to maintain normal physiological functions. Dysregulation of signaling pathways that results in disturbing this balance can lead to the development of cancer. Numerous studies have focused on the activation processes of signaling pathways, which are often mediated by protein kinases. However, considerably less evidence is available concerning how and when the signals are shut off by protein phosphatases.
My lab focuses on elucidating the functional importance of a novel family of protein phosphatase, PHLPP, in regulating tumorigenesis. We use colon cancer as a model system to study how PHLPP functions in suppressing cancer development and progression. PHLPP belongs to a novel family of Ser/Thr protein phosphatases. There are two isoforms, PHLPP1 and PHLPP2, identified in this family. Following our initial discovery of PHLPP as a protein phosphatase and negative regulator of Akt, we have demonstrated that downregulation of PHLPP occurs at high frequency in colon cancer patients, and re-expression of PHLPP in colon cancer cells inhibits cell proliferation in vitro and tumor growth in vivo, thus supporting a tumor suppressor role of PHLPP. In addition, we have discovered that PHLPP is dynamically regulated by protein ubiquitination and deubiquitination in colon cancer, and PHLPP is tightly regulated by a scaffolding protein Scribble.
The long-term goal of my lab is to understand the physiological function of PHLPP and the molecular mechanisms underlying PHLPP-mediated regulation in cancer. To better understand the physiological role of PHLPP in vivo, we have recently developed PHLPP knockout mouse models. We also have a long-standing interest in finding novel substrates of PHLPP. Our studies will aid in developing novel therapeutic strategies in cancer treatment by using PHLPP as a target.

PubMed Publications: 

  • Reyes, G.;Niederst, M.;Cohen-Katsenelson, K.;Stender, J.D.;Kunkel, M.T.;Chen, M.;Brognard, J.;Sierecki, E.;Gao, T.;Nowak, D.G.;Trotman, L.C.;Glass, C.K.;Newton, A.C. "Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output." Proceedings of the National Academy of Sciences of the United States of America 111, 38 (2014): E3957-65. [PubMed Link] | [ Full text ]
  • Jiang, K.;Liu, Y.;Fan, J.;Epperly, G.;Gao, T.;Jiang, J.;Jia, J. "Hedgehog-regulated atypical PKC promotes phosphorylation and activation of Smoothened and Cubitus interruptus in Drosophila." Proceedings of the National Academy of Sciences of the United States of America 111, 45 (2014): E4842-50. [PubMed Link] | [ Full text ]
  • Li, X.;Stevens, P.D.;Liu, J.;Yang, H.;Wang, W.;Wang, C.;Zeng, Z.;Schmidt, M.D.;Yang, M.;Lee, E.Y.;Gao, T. "PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice." Gastroenterology 146, 5 (2014): 1301-12.e1-10. [PubMed Link] | [ Full text ]
  • Zaytseva, Y.Y.;Elliott, V.A.;Rychahou, P.;Mustain, W.C.;Kim, J.T.;Valentino, J.;Gao, T.;O'Connor, K.L.;Neltner, J.M.;Lee, E.Y.;Weiss, H.L.;Evers, B.M. "Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer." Carcinogenesis 35, 6 (2014): 1341-51. [PubMed Link] | [ Full text ]
  • Li, X.;Gao, T. "mTORC2 phosphorylates protein kinase Cζ to regulate its stability and activity." EMBO reports 15, 2 (2014): 191-8. [PubMed Link] | [ Full text ]
  • Wen, Y.A.;Stevens, P.D.;Gasser, M.L.;Andrei, R.;Gao, T. "Downregulation of PHLPP expression contributes to hypoxia-induced resistance to chemotherapy in colon cancer cells." Molecular and cellular biology 33, 22 (2013): 4594-605. [PubMed Link] | [ Full text ]
  • Li, X.;Stevens, P.D.;Yang, H.;Gulhati, P.;Wang, W.;Evers, B.M.;Gao, T. "The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer." Oncogene 32, 4 (2013): 471-8. [PubMed Link] | [ Full text ]
  • Liu, J.;Stevens, P.D.;Eshleman, N.E.;Gao, T. "Protein phosphatase PPM1G regulates protein translation and cell growth by dephosphorylating 4E binding protein 1 (4E-BP1)." The Journal of biological chemistry 288, 32 (2013): 23225-33. [PubMed Link] | [ Full text ]
  • Gulhati, P.;Zaytseva, Y.Y.;Valentino, J.D.;Stevens, P.D.;Kim, J.T.;Sasazuki, T.;Shirasawa, S.;Lee, E.Y.;Weiss, H.L.;Dong, J.;Gao, T.;Evers, B.M. "Sorafenib enhances the therapeutic efficacy of rapamycin in colorectal cancers harboring oncogenic KRAS and PIK3CA." Carcinogenesis 33, 9 (2012): 1782-90. [PubMed Link] | [ Full text ]
  • Valentino, J.D.;Elliott, V.A.;Zaytseva, Y.Y.;Rychahou, P.G.;Mustain, W.C.;Wang, C.;Gao, T.;Evers, B.M. "Novel small interfering RNA cotargeting strategy as treatment for colorectal cancer." Surgery 152, 2 (2012): 277-85. [PubMed Link] | [ Full text ]
  • Li, J.;Song, J.;Cassidy, M.G.;Rychahou, P.;Starr, M.E.;Liu, J.;Li, X.;Epperly, G.;Weiss, H.L.;Townsend CM, J.;Gao, T.;Evers, B.M. "PI3K p110α/Akt signaling negatively regulates secretion of the intestinal peptide neurotensin through interference of granule transport." Molecular endocrinology (Baltimore, Md.) 26, 8 (2012): 1380-93. [PubMed Link] | [ Full text ]
  • Patterson, S.J.;Han, J.M.;Garcia, R.;Assi, K.;Gao, T.;O'Neill, A.;Newton, A.C.;Levings, M.K. "Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells." Journal of immunology (Baltimore, Md. : 1950) 186, 10 (2011): 5533-7. [PubMed Link] | [ Full text ]
  • Gulhati, P.;Bowen, K.A.;Liu, J.;Stevens, P.D.;Rychahou, P.G.;Chen, M.;Lee, E.Y.;Weiss, H.L.;O'Connor, K.L.;Gao, T.;Evers, B.M. "mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways." Cancer research 71, 9 (2011): 3246-56. [PubMed Link] | [ Full text ]
  • Li, X.;Yang, H.;Liu, J.;Schmidt, M.D.;Gao, T. "Scribble-mediated membrane targeting of PHLPP1 is required for its negative regulation of Akt." EMBO reports 12, 8 (2011): 818-24. [PubMed Link] | [ Full text ]
  • Li, J.;Liu, J.;Song, J.;Wang, X.;Weiss, H.L.;Townsend CM, J.;Gao, T.;Evers, B.M. "mTORC1 inhibition increases neurotensin secretion and gene expression through activation of the MEK/ERK/c-Jun pathway in the human endocrine cell line BON." American journal of physiology. Cell physiology 301, 1 (2011): C213-26. [PubMed Link] | [ Full text ]
  • Liu, J.;Stevens, P.D.;Gao, T. "mTOR-dependent regulation of PHLPP expression controls the rapamycin sensitivity in cancer cells." The Journal of biological chemistry 286, 8 (2011): 6510-20. [PubMed Link] | [ Full text ]
  • Liu, J.;Stevens, P.D.;Li, X.;Schmidt, M.D.;Gao, T. "PHLPP-mediated dephosphorylation of S6K1 inhibits protein translation and cell growth." Molecular and cellular biology 31, 24 (2011): 4917-27. [PubMed Link] | [ Full text ]
  • Masubuchi, S.;Gao, T.;O'Neill, A.;Eckel-Mahan, K.;Newton, A.C.;Sassone-Corsi, P. "Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock." Proceedings of the National Academy of Sciences of the United States of America 107, 4 (2010): 1642-7. [PubMed Link] | [ Full text ]
  • Larson, Y.;Liu, J.;Stevens, P.D.;Li, X.;Li, J.;Evers, B.M.;Gao, T. "Tuberous sclerosis complex 2 (TSC2) regulates cell migration and polarity through activation of CDC42 and RAC1." The Journal of biological chemistry 285, 32 (2010): 24987-98. [PubMed Link] | [ Full text ]
  • Miyamoto, S.;Purcell, N.H.;Smith, J.M.;Gao, T.;Whittaker, R.;Huang, K.;Castillo, R.;Glembotski, C.C.;Sussman, M.A.;Newton, A.C.;Brown, J.H. "PHLPP-1 negatively regulates Akt activity and survival in the heart." Circulation research 107, 4 (2010): 476-84. [PubMed Link] | [ Full text ]
  • Cai, Q.;Li, J.;Gao, T.;Xie, J.;Evers, B.M. "Protein kinase Cdelta negatively regulates hedgehog signaling by inhibition of Gli1 activity." The Journal of biological chemistry 284, 4 (2009): 2150-8. [PubMed Link] | [ Full text ]
  • Liu, J.;Weiss, H.L.;Rychahou, P.;Jackson, L.N.;Evers, B.M.;Gao, T. "Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis." Oncogene 28, 7 (2009): 994-1004. [PubMed Link] | [ Full text ]
  • Gulhati, P.;Cai, Q.;Li, J.;Liu, J.;Rychahou, P.G.;Qiu, S.;Lee, E.Y.;Silva, S.R.;Bowen, K.A.;Gao, T.;Evers, B.M. "Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 15, 23 (2009): 7207-16. [PubMed Link] | [ Full text ]
  • Li, X.;Liu, J.;Gao, T. "beta-TrCP-mediated ubiquitination and degradation of PHLPP1 are negatively regulated by Akt." Molecular and cellular biology 29, 23 (2009): 6192-205. [PubMed Link] | [ Full text ]
  • Johnson, S.M.;Gulhati, P.;Arrieta, I.;Wang, X.;Uchida, T.;Gao, T.;Evers, B.M. "Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling." Anticancer research 29, 8 (2009): 3185-90. [PubMed Link] | [ Full text ]
  • Gao, T.;Brognard, J.;Newton, A.C. "The phosphatase PHLPP controls the cellular levels of protein kinase C." The Journal of biological chemistry 283, 10 (2008): 6300-11. [PubMed Link] | [ Full text ]
  • Chen, D.;Gould, C.;Garza, R.;Gao, T.;Hampton, R.Y.;Newton, A.C. "Amplitude control of protein kinase C by RINCK, a novel E3 ubiquitin ligase." The Journal of biological chemistry 282, 46 (2007): 33776-87. [PubMed Link] | [ Full text ]
  • Brognard, J.;Sierecki, E.;Gao, T.;Newton, A.C. "PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms." Molecular cell 25, 6 (2007): 917-31. [PubMed Link] |
  • Gao, T.;Newton, A.C. "Invariant Leu preceding turn motif phosphorylation site controls the interaction of protein kinase C with Hsp70." The Journal of biological chemistry 281, 43 (2006): 32461-8. [PubMed Link] | [ Full text ]
  • Gao, T.;Furnari, F.;Newton, A.C. "PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth." Molecular cell 18, 1 (2005): 13-24. [PubMed Link] |
  • Gao, T.;Newton, A.C. "The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C." The Journal of biological chemistry 277, 35 (2002): 31585-92. [PubMed Link] | [ Full text ]
  • Sonnenburg, E.D.;Gao, T.;Newton, A.C. "The phosphoinositide-dependent kinase, PDK-1, phosphorylates conventional protein kinase C isozymes by a mechanism that is independent of phosphoinositide 3-kinase." The Journal of biological chemistry 276, 48 (2001): 45289-97. [PubMed Link] | [ Full text ]
  • Gao, T.;Cuadra, A.E.;Ma, H.;Bunemann, M.;Gerhardstein, B.L.;Cheng, T.;Eick, R.T.;Hosey, M.M. "C-terminal fragments of the alpha 1C (CaV1.2) subunit associate with and regulate L-type calcium channels containing C-terminal-truncated alpha 1C subunits." The Journal of biological chemistry 276, 24 (2001): 21089-97. [PubMed Link] | [ Full text ]
  • Gao, T.;Toker, A.;Newton, A.C. "The carboxyl terminus of protein kinase c provides a switch to regulate its interaction with the phosphoinositide-dependent kinase, PDK-1." The Journal of biological chemistry 276, 22 (2001): 19588-96. [PubMed Link] | [ Full text ]
  • Gao, T.;Hosey, M.M. "Association of L-type calcium channels with a vacuolar H(+)-ATPase G2 subunit." Biochemical and biophysical research communications 277, 3 (2000): 611-6. [PubMed Link] | [ Full text ]
  • Gerhardstein, B.L.;Gao, T.;Bünemann, M.;Puri, T.S.;Adair, A.;Ma, H.;Hosey, M.M. "Proteolytic processing of the C terminus of the alpha(1C) subunit of L-type calcium channels and the role of a proline-rich domain in membrane tethering of proteolytic fragments." The Journal of biological chemistry 275, 12 (2000): 8556-63. [PubMed Link] | [ Full text ]
  • Gao, T.;Bunemann, M.;Gerhardstein, B.L.;Ma, H.;Hosey, M.M. "Role of the C terminus of the alpha 1C (CaV1.2) subunit in membrane targeting of cardiac L-type calcium channels." The Journal of biological chemistry 275, 33 (2000): 25436-44. [PubMed Link] | [ Full text ]
  • Bünemann, M.;Gerhardstein, B.L.;Gao, T.;Hosey, M.M. "Functional regulation of L-type calcium channels via protein kinase A-mediated phosphorylation of the beta(2) subunit." The Journal of biological chemistry 274, 48 (1999): 33851-4. [PubMed Link] | [ Full text ]
  • Gao, T.;Chien, A.J.;Hosey, M.M. "Complexes of the alpha1C and beta subunits generate the necessary signal for membrane targeting of class C L-type calcium channels." The Journal of biological chemistry 274, 4 (1999): 2137-44. [PubMed Link] | [ Full text ]
  • Chien, A.J.;Gao, T.;Perez-Reyes, E.;Hosey, M.M. "Membrane targeting of L-type calcium channels. Role of palmitoylation in the subcellular localization of the beta2a subunit." The Journal of biological chemistry 273, 36 (1998): 23590-7. [PubMed Link] | [ Full text ]
  • Meyers, M.B.;Puri, T.S.;Chien, A.J.;Gao, T.;Hsu, P.H.;Hosey, M.M.;Fishman, G.I. "Sorcin associates with the pore-forming subunit of voltage-dependent L-type Ca2+ channels." The Journal of biological chemistry 273, 30 (1998): 18930-5. [PubMed Link] | [ Full text ]
  • Gao, T.;Yatani, A.;Dell'Acqua, M.L.;Sako, H.;Green, S.A.;Dascal, N.;Scott, J.D.;Hosey, M.M. "cAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits." Neuron 19, 1 (1997): 185-96. [PubMed Link] |
  • Gao, T.;Puri, T.S.;Gerhardstein, B.L.;Chien, A.J.;Green, R.D.;Hosey, M.M. "Identification and subcellular localization of the subunits of L-type calcium channels and adenylyl cyclase in cardiac myocytes." The Journal of biological chemistry 272, 31 (1997): 19401-7. [PubMed Link] | [ Full text ]
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