Abstract 3464: CBAP: A novel rheostat molecule for regulation of TSC GAP activity and mTORC1 signaling in cancer cells

The PI3K-mTOR signaling pathway is one of the most frequently dysregulated signaling cascades in cancer. Understanding the molecular wiring of the PI3K-mTOR signaling network and its activation in cancer will improve our understanding of their contribution to cancer pathology and provide novel therapeutic strategies by targeting this network. Our previous works demonstrated that Common receptor Beta chain Associated Protein (CBAP) is required for Jurkat cell leukemogenesis and regulates Akt-dependent TSC2 phosphorylation and lysosomal dissociation of TSC complexes, and in turn enhances mTORC1 signalling and expression of c-MYC and HIF-1a in Jurkat T-ALL leukemic cells. In this report, we tackle the question how TSC/Rheb/mTORC1 pathway is regulated by CBAP via cell-based functional assay, immunoprecipitation and in vitro GTPase assay. Our data revealed that CBAP interacted with TSC2 via tuberin-binding domain and could compete for TSC2 binding with TSC1 and suppressed the GTPase activation activity of TSC1/2 complexes. Akt could also associate with TSC2 complexes and CBAP in both Jurkat and CBAP-knockout Jurkat cells, except that TSC1 could be detected within the complexes only in the absence of CBAP. Moreover, the Rheb-GAP activity of this Akt-associated TSC2 complexes was sensitive to the presence of CBAP and TSC1/2 GAP activity was strongly suppressed by recombinant CBAP proteins in the in vitro reconstituted assay. Finally, a peptide domain of CBAP interacting with TSC2 was mapped and disruption of CBAP-TSC2 interaction by overexpressing this peptide inhibits the Akt/Rheb signal axis and suppresses leukemia cell growth. In summary, our data revealed an important role of the interaction between CBAP and TSC2 proteins in promoting Rheb/mTORC1 signaling activity, and suggested a crucial role of overexpression of CBAP protein in tumor cell proliferation. Citation Format: Jong-Young J. Yen, Yun-Jung Chiang, Wei-Ting Liao, Shih-Hao Wang, Hsin-Fang Yang-Yen. CBAP: A novel rheostat molecule for regulation of TSC GAP activity and mTORC1 signaling in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3464.