Absence And/Or Functional Loss Of The Tumor Suppressor Tnk1 Is Associated With Various Human Neoplasms

The protein tyrosine kinase activity of Tnk1 (Thirty-eight negative kinase) is required for cell growth suppression due to the fact that the kinase-dead Tnk1 triggers aberrant cell growth, including anchorage independent growth with hyperactivation of Ras (Hoare et. al. 2003; Azoitie et.al. 2007). Mechanistically, the cell growth suppression is associated with the inhibition of Ras activity and the down-stream Raf1-MAPK growth pathway (Hoare et.al. 2003) resulting in G2-M phase cell cycle arrest. A tumor suppressor role of Tnk1 was subsequently confirmed by developing the Tnk1 knockout mouse model by homologous recombination. The TNK1 knockout mice develop many types of tumors upon aging, with B-cell lymphomas, hepatomas, hepatocellular carcinomas, lung adenomas and adenocarcinomas being the most frequent malignancies (Hoare et.al. 2008; May et. al. 2010). Significantly, 40% of Tnk1-/-mice and 26% of Tnk1+/− mice had more than one tumor type develop, likely reflecting Tnk19s broad tumor suppressor function. To confirm the tumor suppressor function of the 72 kDa Tnk1 in human tumors and cell lines, we screened for Tnk19s expression and analyzed its intrinsic/auto kinase activity and in vitro kinase activity. Results indicate that in tumors and cell lines, Tnk1 is either expressed or absent. In B-/T-lymphoma and lung adenocarcinoma cell lines, to name a few, such as Ramos, Jurkat, REH and A549, absence of Tnk1 is associated with aberrant Ras activity, suggesting that loss of Tnk1 expression may contribute to tumor development. In patient specimens and cell lines namely, K562, T47D, MCF7, NCI H82, NCI H387, HEPG2 and HUH, the expressed Tnk1 is found to lack auto-kinase activity and is therefore, inactive in vivo. This data indicates that tumor growth depends on the maintenance of Tnk1 in its inactive form through interaction(s) with scaffolding protein(s) and/or due to SNPs found in its kinase domain. Strikingly, the Hodgkin lymphoma cell line L540 is found to express a tyrosine phosphorylated 60 kDa truncated Tnk-(C17ORF61) fusion gene product (termed tTnk1) raising doubt that it is an activated form of Tnk1 (Gu et. al. 2010). Interestingly, we found that t-Tnk1 is kinase-dead, as it fails to Y-phosphorylate Grb2, a Tnk1 substrate. This supports the concept that t-Tnk1 and/or functionally inactive Tnk1 expressed in tumor cells may function in a dominant negative manner to maintain tumor growth. In conclusion, Tnk1, in human, also functions as a tumor suppressor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4181. doi:1538-7445.AM2012-4181