Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Vimentin is a novel AKT1 target mediating motility and invasion

Oncogene volume 30, pages 457–470 (2011)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Ackah E, Yu J, Zoellner S, Iwakiri Y, Skurk C, Shibata R et al. (2005). Akt1/protein kinase Balpha is critical for ischemic and VEGF-mediated angiogenesis. J Clin Invest 115: 2119–2127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE, Ayala R et al. (2003). Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res 63: 196–206.

    CAS  PubMed  Google Scholar 

  • Bhattacharya R, Gonzalez AM, Debiase PJ, Trejo HE, Goldman RD, Flitney FW et al. (2009). Recruitment of vimentin to the cell surface by beta3 integrin and plectin mediates adhesion strength. J Cell Sci 122: 1390–1400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bodenstine TM, Welch DR . (2008). Metastasis suppressors and the tumor microenvironment. Cancer Microenviron 1: 1–11.

    Article  PubMed  PubMed Central  Google Scholar 

  • Broers JL, de Leij L, Rot MK, ter Haar A, Lane EB, Leigh IM et al. (1989). Expression of intermediate filament proteins in fetal and adult human lung tissues. Differentiation 40: 119–128.

    Article  CAS  PubMed  Google Scholar 

  • Byun Y, Chen F, Chang R, Trivedi M, Green KJ, Cryns VL . (2001). Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis. Cell Death Differ 8: 443–450.

    Article  CAS  PubMed  Google Scholar 

  • Clark MA, Fisher C, Judson I, Thomas JM . (2005). Soft-tissue sarcomas in adults. N Engl J Med 353: 701–711.

    Article  CAS  PubMed  Google Scholar 

  • Colucci-Guyon E, Portier MM, Dunia I, Paulin D, Pournin S, Babinet C . (1994). Mice lacking vimentin develop and reproduce without an obvious phenotype. Cell 79: 679–694.

    Article  CAS  PubMed  Google Scholar 

  • Eckes B, Dogic D, Colucci-Guyon E, Wang N, Maniotis A, Ingber D et al. (1998). Impaired mechanical stability, migration and contractile capacity in vimentin-deficient fibroblasts. J Cell Sci 111 (Part 13): 1897–1907.

    CAS  PubMed  Google Scholar 

  • Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H et al. (2007). Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem 282: 11221–11229.

    Article  CAS  PubMed  Google Scholar 

  • Goto H, Kosako H, Tanabe K, Yanagida M, Sakurai M, Amano M et al. (1998). Phosphorylation of vimentin by Rho-associated kinase at a unique amino-terminal site that is specifically phosphorylated during cytokinesis. J Biol Chem 273: 11728–11736.

    Article  CAS  PubMed  Google Scholar 

  • Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W et al. (2003). The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 63: 2172–2178.

    CAS  PubMed  Google Scholar 

  • Gu YM, Jin YH, Choi JK, Baek KH, Yeo CY, Lee KY . (2006). Protein kinase A phosphorylates and regulates dimerization of 14-3-3 epsilon. FEBS Lett 580: 305–310.

    Article  CAS  PubMed  Google Scholar 

  • Hendrix MJ, Seftor EA, Seftor RE, Trevor KT . (1997). Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. Am J Pathol 150: 483–495.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hernando E, Charytonowicz E, Dudas ME, Menendez S, Matushansky I, Mills J et al. (2007). The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med 13: 748–753.

    Article  CAS  PubMed  Google Scholar 

  • Hutchinson JN, Jin J, Cardiff RD, Woodgett JR, Muller WJ . (2004). Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res 64: 3171–3178.

    Article  CAS  PubMed  Google Scholar 

  • Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N et al. (2005). Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol 171: 1023–1034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ivaska J, Vuoriluoto K, Huovinen T, Izawa I, Inagaki M, Parker PJ . (2005). PKCepsilon-mediated phosphorylation of vimentin controls integrin recycling and motility. EMBO J 24: 3834–3845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ju X, Katiyar S, Wang C, Liu M, Jiao X, Li S et al. (2007). Akt1 governs breast cancer progression in vivo. Proc Natl Acad Sci USA 104: 7438–7443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanda S, Miyata Y, Kanetake H . (2004). Fibroblast growth factor-2-mediated capillary morphogenesis of endothelial cells requires signals via Flt-1/vascular endothelial growth factor receptor-1: possible involvement of c-Akt. J Biol Chem 279: 4007–4016.

    Article  CAS  PubMed  Google Scholar 

  • Kim MA, Lee HS, Lee HE, Kim JH, Yang HK, Kim WH . (2009). Prognostic importance of epithelial-mesenchymal transition-related protein expression in gastric carcinoma. Histopathology 54: 442–451.

    Article  PubMed  Google Scholar 

  • Liu H, Radisky DC, Nelson CM, Zhang H, Fata JE, Roth RA et al. (2006). Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. Proc Natl Acad Sci USA 103: 4134–4139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo M, Langlais P, Yi Z, Lefort N, De Filippis EA, Hwang H et al. (2007). Phosphorylation of human insulin receptor substrate-1 at Serine 629 plays a positive role in insulin signaling. Endocrinology 148: 4895–4905.

    Article  CAS  PubMed  Google Scholar 

  • Maroulakou IG, Oemler W, Naber SP, Tsichlis PN . (2007). Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res 67: 167–177.

    Article  CAS  PubMed  Google Scholar 

  • McInroy L, Maatta A . (2007). Down-regulation of vimentin expression inhibits carcinoma cell migration and adhesion. Biochem Biophys Res Commun 360: 109–114.

    Article  CAS  PubMed  Google Scholar 

  • Menet V, Gimenez y Ribotta M, Chauvet N, Drian MJ, Lannoy J, Colucci-Guyon E et al. (2001). Inactivation of the glial fibrillary acidic protein gene, but not that of vimentin, improves neuronal survival and neurite growth by modifying adhesion molecule expression. J Neurosci 21: 6147–6158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyazaki T, Honda K, Ohata H . (2007). Requirement of Ca2+ influx- and phosphatidylinositol 3-kinase-mediated m-calpain activity for shear stress-induced endothelial cell polarity. Am J Physiol Cell Physiol 293: C1216–25.

    Article  CAS  PubMed  Google Scholar 

  • Morishima N . (1999). Changes in nuclear morphology during apoptosis correlate with vimentin cleavage by different caspases located either upstream or downstream of Bcl-2 action. Genes Cells 4: 401–414.

    Article  CAS  PubMed  Google Scholar 

  • Nelson WJ, Traub P . (1983). Proteolysis of vimentin and desmin by the Ca2+-activated proteinase specific for these intermediate filament proteins. Mol Cell Biol 3: 1146–1156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Phung TL, Ziv K, Dabydeen D, Eyiah-Mensah G, Riveros M, Perruzzi C et al. (2006). Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10: 159–170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pittenger JT, Hess JF, Budamagunta MS, Voss JC, Fitzgerald PG . (2008). Identification of phosphorylation-induced changes in vimentin intermediate filaments by site-directed spin labeling and electron paramagnetic resonance. Biochemistry 47: 10863–10870.

    Article  CAS  PubMed  Google Scholar 

  • Qi XJ, Wildey GM, Howe PH . (2006). Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem 281: 813–823.

    Article  CAS  PubMed  Google Scholar 

  • Sin WC, Chen XQ, Leung T, Lim L . (1998). RhoA-binding kinase alpha translocation is facilitated by the collapse of the vimentin intermediate filament network. Mol Cell Biol 18: 6325–6339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sulis ML, Parsons R . (2003). PTEN: from pathology to biology. Trends Cell Biol 13: 478–483.

    Article  CAS  PubMed  Google Scholar 

  • Sumitani S, Goya K, Testa JR, Kouhara H, Kasayama S . (2002). Akt1 and Akt2 differently regulate muscle creatine kinase and myogenin gene transcription in insulin-induced differentiation of C2C12 myoblasts. Endocrinology 143: 820–828.

    Article  CAS  PubMed  Google Scholar 

  • Tanno S, Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR . (2001). AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 61: 589–593.

    CAS  PubMed  Google Scholar 

  • Tomita Y, Morooka T, Hoshida Y, Zhang B, Qiu Y, Nakamichi I et al. (2006). Prognostic significance of activated AKT expression in soft-tissue sarcoma. Clin Cancer Res 12: 3070–3077.

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Weinberg RA . (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14: 818–829.

    Article  CAS  PubMed  Google Scholar 

  • Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S, Toker A . (2005). Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 20: 539–550.

    Article  CAS  PubMed  Google Scholar 

  • Zhu QS, Ren W, Korchin B, Lahat G, Dicker A, Lu Y et al. (2008). Soft tissue sarcoma cells are highly sensitive to AKT blockade: a role for p53-independent up-regulation of GADD45 alpha. Cancer Res 68: 2895–2903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Q-S Zhu, K-L Huang, G Lahat, S Bolshakov, T Nguyen, R Belousov & K Bill

  2. Center for Proteomics, The University of Texas Brown Foundation Institute of Molecular Medicine, TX, USA

    K Rosenblatt & R Brobey

  3. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Z Ding & G B Mills

  4. Mass Spectrometry Core Lab, The University of Texas Medical Branch, Galveston, TX, USA

    X Luo

  5. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Lazar

  6. Department of Radiation Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    A Dicker

  7. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M-C Hung

  8. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan

    M-C Hung

  9. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D Lev

Authors
  1. Q-S Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Rosenblatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K-L Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Lahat
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Brobey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Bolshakov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Z Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R Belousov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K Bill
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. X Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A Lazar
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A Dicker
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. G B Mills
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M-C Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. D Lev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Lev.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, QS., Rosenblatt, K., Huang, KL. et al. Vimentin is a novel AKT1 target mediating motility and invasion. Oncogene 30, 457–470 (2011). https://doi.org/10.1038/onc.2010.421

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.421

Keywords

This article is cited by

Search

Advanced search

Quick links