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Vimentin is a novel AKT1 target mediating motility and invasion


The PI3K/AKT signaling pathway is aberrant in a wide variety of cancers. Downstream effectors of AKT are involved in survival, growth and metabolic-related pathways. In contrast, contradictory data relating to AKT effects on cell motility and invasion, crucial prometastatic processes, have been reported pointing to a potential cell type and isoform type-specific AKT-driven function. By implication, study of AKT signaling should optimally be conducted in an appropriate intracellular environment. Prognosis in soft-tissue sarcoma (STS), the aggressive malignancies of mesenchymal origin, is poor, reflecting our modest ability to control metastasis, an effort hampered by lack of insight into molecular mechanisms driving STS progression and dissemination. We examined the impact of the cancer progression-relevant AKT pathway on the mesenchymal tumor cell internal milieu. We demonstrate that AKT1 activation induces STS cell motility and invasiveness at least partially through a novel interaction with the intermediate filament vimentin (Vim). The binding of AKT (tail region) to Vim (head region) results in Vim Ser39 phosphorylation enhancing the ability of Vim to induce motility and invasion while protecting Vim from caspase-induced proteolysis. Moreover, vimentin phosphorylation was shown to enhance tumor and metastasis growth in vivo. Insights into this mesenchymal-related molecular mechanism may facilitate the development of critically lacking therapeutic options for these devastating malignancies.

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We thank Dr Giranda (Abbot Laboratories, Abbott Park, IL) for providing A674563 (A563), Dr Cryns (Division of Endocrinology, Northwestern University, Chicago, IL) for providing human Vim cDNA and Dr Fletcher (Brigham and Women's Hospital, Boston, MA) for the MPNST724 cell line. We thank the UTMB NHLBI Proteomic Center for assistance with mass spectrometry experiments. (The work was supported by the NIH/NHLBI proteomics Initiative NO1-HV-28184 (to KPR).) Vu is thanked for aid in figure preparation and Lo for her assistance with scientific editing. This paper was supported in part by NIH RO1 Grant CA138345 and a RTOG seed grant (to DL). Dr Rosenblatt is a recipient of a Welch Foundation Endowment in Chemistry and Related Science Fellowship award (Grant # L-AU-0002). All experiments conducted at UT-MDACC Core Facilities were further supported by an NCI Cancer Center Support Grant (CA#16672). Financial Support: This paper was supported by NIH/NCI RO1 Grant CA138345 and an RTOG seed grant (to DL), and by NIH/NHLBI proteomics Initiative grant NO1-HV-28184 (to KPR).

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Zhu, QS., Rosenblatt, K., Huang, KL. et al. Vimentin is a novel AKT1 target mediating motility and invasion. Oncogene 30, 457–470 (2011).

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