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Vimentin is a novel AKT1 target mediating motility and invasion.

Oncogene | Jan 27, 2011

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.

Pubmed ID: 20856200 RIS Download

Mesh terms: Animals | Blotting, Western | Cell Line, Tumor | Cell Movement | Fluorescent Antibody Technique | Humans | Immunoprecipitation | Mesoderm | Mice | Mice, SCID | Neoplasm Invasiveness | Proto-Oncogene Proteins c-akt | Sarcoma | Signal Transduction | Soft Tissue Neoplasms | Transfection | Vimentin

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Associated grants

  • Agency: NHLBI NIH HHS, Id: N01HV28184
  • Agency: NCI NIH HHS, Id: R01 CA138345
  • Agency: NHLBI NIH HHS, Id: N01-HV-28184
  • Agency: NCI NIH HHS, Id: CA138345
  • Agency: NCI NIH HHS, Id: R01 CA138345-02

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Scansite searches for motifs within proteins that are likely to be phosphorylated by specific protein kinases or bind to domains such as SH2 domains, 14-3-3 domains or PDZ domains. The Motifscanner program utilizes an entropy approach that assesses the probability of a site matching the motif using the selectivity values and sums the logs of the probability values for each amino acid in the candidate sequence. The program then indicates the percentile ranking of the candidate motif in respect to all potential motifs in proteins of a protein database. When available, percentile scores of some confirmed phosphorylation sites for the kinase of interests or confirmed binding sites of the domain of interest are provided for comparison with the scores of the candidate motifs.

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Fisher Center For Alzheimers Research Foundation: ALZinfo.org

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