The long term goal of the proposed research is to elucidate the molecular mechanism of protein phosphatase mediated regulation of protein kinase C and Akt. Protein kinase C and Akt belong to the AGC kinase superfamily. Both kinases have been shown to play critical roles in modulating tumorigenesis process. Both kinases are regulated by a multi-step phosphorylation process. While phosphorylation of the kinases is important for the enzyme activity, dephosphorylation is associated with enzyme inactivation and downregulation. However, little is known about the dephosphorylation process of protein kinase C and Akt. We have recently identified a novel pleckstrin homology containing protein phosphatase, SCOP. Preliminary studies have indicated that this phosphatase dephosphorylates protein kinase C and Akt both in vitro and in vivo. This proposal addresses how SCOP regulates protein kinase C and Akt.
Specific Aims are: ? 1) Regulation of PKC and Akt by SCOP-mediated dephosphorylation in vivo: The goal of this section is to understand the molecular mechanism by which SCOP dephosphorylates PKC and Akt in cells. Specifically, whether the activity of SCOP requires membrane binding and lipid signaling will be investigated. ? 2) Functional significance of SCOP-mediated dephosphorylation: Expression level of endogenous SCOP will be knocked down using siRNA approach, and functional changes of protein kinase C and Akt will be studied. ? 3) Regulation of SCOP by protein:protein interactions: The goal of this section is to understand how protein:protein interactions between SCOP and protein kinase C or Akt, and between SCOP and other cellular proteins affect SCOP function. ? ? My long-term career goal is to become an independent scientific investigator in the field of cancer biology research. Specifically, I am interested in studying the molecular mechanisms of cancer. To achieve this goal, my short-term plan is to gain more research experience in a well established laboratory at a top academic institute. Dr. Newton's lab at UCSD will provide me with the additional training that I need to develop my career further. With the support by this grant, I will have the opportunity to work independently and develop my own research plan. Meanwhile, I will be greatly benefited from the outstanding research facilities provided by Dr. Newton and UCSD, and from scientific communications with the faculty members at UCSD. ? ?
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| Gulhati, Pat; Cai, Qingsong; Li, Jing et al. (2009) Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer. Clin Cancer Res 15:7207-16 |
| Johnson, Sara M; Gulhati, Pat; Arrieta, Isela et al. (2009) Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling. Anticancer Res 29:3185-90 |
