Akt Pathway Activation by Human T-cell Leukemia Virus Type 1 Tax Oncoprotein

• Published in: The Journal of biological chemistry Vol. 290; no. 43; pp. 26270 - 26281
• Main Authors: Cherian, Mathew A., Baydoun, Hicham H., Al-Saleem, Jacob, Shkriabai, Nikoloz, Kvaratskhelia, Mamuka, Green, Patrick, Ratner, Lee
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.10.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Akt PKB; Amino Acid Sequence; Enzyme Activation; Gene Products, tax - chemistry; Gene Products, tax - metabolism; HEK293 Cells; Human T-lymphotropic virus 1 - metabolism; Humans; Microbiology; Molecular Sequence Data; NF-kappa B - metabolism; PDZ domain; phosphatase and tensin homolog (PTEN); protein serine/threonine phosphatase (PSP); Proto-Oncogene Proteins c-akt - metabolism; retrovirus; Tandem Mass Spectrometry; phosphatase and tensin homolog (PTEN); protein serine/threonine phosphatase (PSP); retrovirus; PDZ domain; Akt PKB
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.684746

Human T-cell leukemia virus (HTLV) type 1, the etiological agent of adult T-cell leukemia, expresses the viral oncoprotein Tax1. In contrast, HTLV-2, which expresses Tax2, is non-leukemogenic. One difference between these homologous proteins is the presence of a C-terminal PDZ domain-binding motif (PBM) in Tax1, previously reported to be important for non-canonical NFκB activation. In contrast, this study finds no defect in non-canonical NFκB activity by deletion of the Tax1 PBM. Instead, Tax1 PBM was found to be important for Akt activation. Tax1 attenuates the effects of negative regulators of the PI3K-Akt-mammalian target of rapamycin pathway, phosphatase and tensin homologue (PTEN), and PHLPP. Tax1 competes with PTEN for binding to DLG-1, unlike a PBM deletion mutant of Tax1. Forced membrane expression of PTEN or PHLPP overcame the effects of Tax1, as measured by levels of Akt phosphorylation, and rates of Akt dephosphorylation. The current findings suggest that Akt activation may explain the differences in transforming activity of HTLV-1 and -2. Background: HTLV-1, not HTLV-2, is leukemogenic, and its oncoprotein, Tax1, includes a PDZ domain-binding motif (PBM). Results: Tax1 induces Akt phosphorylation dependent on the PBM, which is overcome by membrane expression of PTEN and PHLPP. Conclusion: Tax1 inhibits PI3K-Akt regulatory phosphatases. Significance: Akt activation may contribute to the leukemic potential of HTLV-1 and provides a new therapeutic target.