Abstract
Fer is a nuclear and cytoplasmic intracellular tyrosine kinase. Herein we show that Fer is required for cell-cycle progression in malignant cells. Decreasing the level of Fer using the RNA interference (RNAi) approach impeded the proliferation of prostate and breast carcinoma cells and led to their arrest at the G0/G1 phase. At the molecular level, knockdown of Fer resulted in the activation of the retinoblastoma protein (pRB), and this was reflected by profound hypo-phosphorylation of pRB on both cyclin-dependent kinase CDK4 and CDK2 phosphorylation sites. Dephosphorylation of pRB was not seen upon the direct targeting of either CDK4 or CDK2 expression, and was only partially achieved by the simultaneous depletion of these two kinases. Amino-acid sequence analysis revealed two protein phosphatase 1 (PP1) binding motifs in the kinase domain of Fer and the association of Fer with the pRB phosphatase PP1α was verified using co-immunoprecipitation analysis. Downregulation of Fer potentiated the activation of PP1α and overexpression of Fer decreased the enzymatic activity of that phosphatase. Our findings portray Fer as a regulator of cell-cycle progression in malignant cells and as a potential target for cancer intervention.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Alberts AS, Thorburn AM, Shenolikar S, Mumby MC, Feramisco JR . (1993). Proc Natl Acad Sci USA 90: 388–392.
Allard P, Zoubeidi A, Nguyen LT, Tessier S, Tanguay S, Chevrette M et al. (2000). Mol Cell Endocrinol 159: 63–77.
Ayllon V, Cayla X, Garcia A, Fleischer A, Rebollo A . (2002). Eur J Immunol 32: 1847–1855.
Ben-Dor I, Bern O, Tennenbaum T, Nir U . (1999). Cell Growth Differ 10: 113–129.
Bennett D, Alphey L . (2002). Nat Genet 31: 419–423.
Berndt N, Dohadwala M, Liu CW . (1997). Curr Biol 7: 375–386.
Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P . (2003). Curr Biol 13: 1775–1785.
Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA . (1999). Proc Natl Acad Sci USA 96: 1002–1007.
Ceulemans H, Bollen M . (2004). Physiol Rev 84: 1–39.
Ceulemans H, Stalmans W, Bollen M . (2002). BioEssays 24: 371–381.
Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM et al. (1999). EMBO J 18: 1571–1583.
Chow JP, Siu WY, Fung TK, Chan WM, Lau A, Arooz T et al. (2003). Mol Biol Cell 14: 3989–4002.
Connell-Crowley L, Harper JW, Goodrich DW . (1997). Mol Biol Cell 8: 287–301.
Coqueret O . (2003). Trends Cell Biol 13: 65–70.
Craig AW, Greer PA . (2002). Mol Cell Biol 22: 6363–6374.
Craig AW, Zirngibl R, Williams K, Cole LA, Greer PA . (2001). Mol Cell Biol 21: 603–613.
Dohadwala M, da Cruz e Silva EF, Hall FL, Williams RT, Carbonaro-Hall DA, Nairn AC et al. (1994). Proc Natl Acad Sci USA 91: 6408–6412.
Durfee T, Becherer K, Chen PL, Yeh SH, Yang Y, Kilburn AE et al. (1993). Genes Dev 7: 555–569.
Egloff MP, Johnson DF, Moorhead G, Cohen PT, Cohen P, Barford D . (1997). EMBO J 16: 1876–1887.
Ezhevsky SA, Nagahara H, Vocero-Akbani AM, Gius DR, Wei MC, Dowdy SF . (1997). Proc Natl Acad Sci USA 94: 10699–10704.
Fischman K, Edman JC, Shackleford GM, Turner JA, Rutter WJ, Nir U . (1990). Mol Cell Biol 10: 146–153.
Garcia A, Cayla X, Guergnon J, Dessauge F, Hospital V, Rebollo MP et al. (2003). Biochimie 85: 721–726.
Greer P . (2002). Nat Rev Mol Cell Biol 3: 278–289.
Hao Q-L, Heisterkamp N, Groffen J . (1989). Mol Cell Biol 9: 1587–1593.
Herrera RE, Sah VP, Williams BO, Makela TP, Weinberg RA, Jacks T . (1996). Mol Cell Biol 16: 2402–2407.
Honkanen RE, Golden T . (2002). Curr Med Chem 9: 2055–2075.
Iwanishi M, Czech MP, Cherniack AD . (2000). J Biol Chem 275: 38995–39000.
Kaldis P . (1999). Cell Mol Life Sci 55: 284–296.
Katayama H, Zhou H, Li Q, Tatsuka M, Sen S . (2001). J Biol Chem 276: 46219–46224.
Kim L, Wong TW . (1998). J Biol Chem 273: 23542–23548.
Kitagawa M, Higashi H, Jung HK, Suzuki-Takahashi I, Ikeda M, Tamai K et al. (1996). EMBO J 15: 7060–7069.
Kogata N, Masuda M, Kamioka Y, Yamagishi A, Endo A, Okada M et al. (2003). Mol Biol Cell 14: 3553–3564.
Kwon YG, Lee SY, Choi Y, Greengard P, Nairn AC . (1997). Proc Natl Acad Sci USA 94: 2168–2173.
Letwin K, Yee S-P, Pawson T . (1988). Oncogene 3: 621–627.
Liu CW, Wang RH, Dohadwala M, Schonthal AH, Villa-Moruzzi E, Berndt N . (1999). J Biol Chem 274: 29470–29475.
Ludlow JW, Glendening CL, Livingston DM, DeCarprio JA . (1993). Mol Cell Biol 13: 367–372.
Lunter PC, Wiche G . (2002). Biochem Biophys Res Commun 296: 904–910.
Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A, Ortega S et al. (2004). Cell 118: 493–504.
Miravet S, Piedra J, Castano J, Raurell I, Franci C, Dunach M et al. (2003). Mol Cell Biol 23: 7391–7402.
Morgenstern JP, Land H . (1990). Nucleic Acids Res 18: 3587–3596.
Naviaux RK, Costanzi E, Haas M, Verma IM . (1996). J Virol 70: 5701–5705.
Orlovsky K, Ben-Dor I, Priel-Halachmi S, Malovany H, Nir U . (2000). Biochemistry 39: 11084–11091.
Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R et al. (2003). Nat Genet 35: 25–31.
Pan W, Sun T, Hoess R, Grafstrom R . (1998). Carcinogenesis 19: 765–769.
Penhallow RC, Class K, Sonoda H, Bolen JB, Rowley RB . (1995). J Biol Chem 270: 23362–23365.
Piedra J, Miravet S, Castano J, Palmer HG, Heisterkamp N, Garcia dH et al. (2003). Mol Cell Biol 23: 2287–2297.
Priel-Halachmi S, Ben-Dor I, Shpungin S, Tennenbaum T, Molavani H, Bachrach M et al. (2000). J Biol Chem 275: 28902–28910.
Reed SI . (1997) In: Kastern M (ed). Checkpoint Controls and Cancer, Cancer Surveys, 29. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY. pp 7–23.
Rosato R, Veltmaat JM, Groffen J, Heisterkamp N . (1998). Mol Cell Biol 18: 5762–5770.
Rubin E, Mittnacht S, Villa-Moruzzi E, Ludlow JW . (2001). Oncogene 20: 3776–3785.
Salem Y, Shpungin S, Pasder O, Pomp O, Taler M, Malovani H et al. (2005). Cell Signal 17: 341–353.
Sellin JH, Umar S, Xiao J, Morris AP . (2001). Cancer Res 61: 2899–2906.
Sherr CJ, Roberts JM . (2004). Genes Dev 18: 2699–2711.
Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R et al. (1999). Proc Natl Acad Sci USA 96: 5522–5527.
Sugiyama K, Sugiura K, Hara T, Sugimoto K, Shima H, Honda K et al. (2002). Oncogene 21: 3103–3111.
Tetsu O, McCormick F . (2003). Cancer Cell 3: 233–245.
Vermeulen K, Van Bockstaele DR, Berneman ZN . (2003). Cell Prolif 36: 131–149.
Wang RH, Liu CW, Avramis VI, Berndt N . (2001). Oncogene 20: 6111–6122.
Yamasaki L . (2003). Cancer Treat Res 115: 209–239.
Zarkowska T, Mittnacht S . (1997). J Biol Chem 272: 12738–12746.
Acknowledgements
We thank Ms Sharon Victor for typing this manuscript and Mr Uri Karo for assistance with the flow-cytometry analysis. This work was supported by grants from CaPCURE Israel, the Ministry of Health Chief Scientist's Research Fund, Deborah Silin and Samuel-Heinrich Winograd Research Fund, the Weinkselbaum Family Research Fund, and a grant from the Horowitz Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pasder, O., Shpungin, S., Salem, Y. et al. Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells. Oncogene 25, 4194–4206 (2006). https://doi.org/10.1038/sj.onc.1209695
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1209695
Keywords
This article is cited by
-
A novel Fer/FerT targeting compound selectively evokes metabolic stress and necrotic death in malignant cells
Nature Communications (2017)
-
The roles and therapeutic potential of cyclin-dependent kinases (CDKs) in sarcoma
Cancer and Metastasis Reviews (2016)
-
FER kinase promotes breast cancer metastasis by regulating α6- and β1-integrin-dependent cell adhesion and anoikis resistance
Oncogene (2013)
-
FES kinases are required for oncogenic FLT3 signaling
Leukemia (2010)
-
Identification of tyrosine-phosphorylated proteins associated with metastasis and functional analysis of FER in human hepatocellular carcinoma cells
BMC Cancer (2009)