Dual specificity Tyrosine (Y)-regulated kinase 1A (DYRK1A) is required for cell cycle arrest in G0/G1 and oncogenic Ras-induced senescence. DYRK1A is often expressed at low levels in cancer cell lines while its overexpression causes growth arrest, suggesting that DYRK1A plays a tumor suppressor role. However, the signaling pathways that involve DYRK1A are not fully understood. To determine the factors that mediate the function of DYRK1A, we performed mass spectroscopy proteomic analysis of the DYRK1A-interacting proteins in human cells. This study revealed a specific and reproducible interaction between DYRK1A and the components of the tuberous sclerosis complex (TSC). The TSC plays a key inhibitory role in control of the protein kinase activity of the mTOR complex 1 (TORC1). TORC1 promotes protein synthesis, cell proliferation and survival in response to growth factors and nutrient stimuli by phosphorylating substrates such as p70 S6K1 and 4E-BP1. Importantly, our preliminary data show that RNAi depletion of DYRK1A leads to an increased TORC1 activity under serum starved conditions. Both DYRK1A and the TSC mediate the processes that control cell proliferation under the nutrient- and growth factor-limiting conditions. However, it is not known whether DYRK1A and the TSC are functionally connected. Given the physical interaction between DYRK1A and the TSC subunits, we propose to determine whether DYRK1A plays a role in the TORC1-inhibitory function of the TSC and to establish the mechanism of this regulation. To determine whether the kinase activity and the biological effects of the TORC1 are indeed regulated by DYRK1A, we will employ loss- and gain-of-function approaches using human cancer cell lines and non-transformed cells. To determine mechanisms that mediate the effects of DYRK1A on the TORC1, we will use biochemical approaches to establish whether DYRK1A-mediated phosphorylation of the TSC could play a role in these processes. The findings obtained in this study could have important implications for cancer pathogenesis because of the recognized tumor suppressor role of the TSC. Mutations in the TSC components cause tuberous sclerosis (TS), a rare genetic syndrome characterized by tumorigenesis and neurological symptoms. TORC1 is often aberrantly activated in human cancers due to mutations in the upstream regulatory pathways; several classes of mTOR-inhibitory drugs are now being evaluated for treatment of cancer and TS. Accurate prediction of the tumor susceptibility or resistance to the mTOR inhibitors will be the key for successful application of these drugs for anti-cancer therapy. Furthermore, characterization of the novel interaction between DYRK1A and the TSC protein complex will help our understanding of the pathogenesis of cancer and TS. This knowledge may reveal new therapeutic opportunities and help to improve selection of patients that will benefit the most from the mTOR-inhibitory therapy.
NIH ExPorter
NIH ExPorter