Small C-terminal Domain Phosphatase Enhances Snail Activity Through Dephosphorylation

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2008 Nov 14

PMID 19004823

Citations 58

Authors

Yadi Wu

B Mark Evers

Binhua P Zhou

Affiliations

Soon will be listed here.

Abstract

Down-regulation of E-cadherin plays an important role in epithelial-mesenchymal transition (EMT), which is critical in normal development and disease states such as tissue fibrosis and metastasis. Snail, a key transcription repressor of E-cadherin, is a labile protein with a short half-life and is regulated through phosphorylation, ubiquitination, and degradation. Previously, we showed that GSK-3beta phosphorylated two stretches of serine residues within the nuclear export signal and the destruction box of Snail, provoking its cytoplasmic export for ubiquitin-mediated proteasome degradation. However, the mechanism of Snail dephosphorylation and the identity of the Snail-specific phosphatase remain elusive. Using a functional genomic screening, we found that the small C-terminal domain phosphatase (SCP) is a specific phosphatase for Snail. SCP interacted and co-localized with Snail in the nucleus. We also found that SCP expression induced Snail dephosphorylation and stabilization in vitro and in vivo. However, a catalytically inactive mutant of SCP had no effect on Snail. Furthermore, we found that Snail stabilization induced by SCP enhanced snail activity in the suppression of E-cadherin and increased cell migration. Thus, our findings indicate that SCP functions as a Snail phosphatase to control its phosphorylation and stabilization, and our study provides novel insights for the regulation of Snail during EMT and cancer metastasis.

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References

Saleque S, Kim J, Rooke H, Orkin S . Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Mol Cell. 2007; 27(4):562-72. DOI: 10.1016/j.molcel.2007.06.039. View

Shi Y, Massague J . Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003; 113(6):685-700. DOI: 10.1016/s0092-8674(03)00432-x. View

Thiery J, Sleeman J . Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006; 7(2):131-42. DOI: 10.1038/nrm1835. View

Valcourt U, Kowanetz M, Niimi H, Heldin C, Moustakas A . TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell. 2005; 16(4):1987-2002. PMC: 1073677. DOI: 10.1091/mbc.e04-08-0658. View

Yamashita S, Miyagi C, Fukada T, Kagara N, Che Y, Hirano T . Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature. 2004; 429(6989):298-302. DOI: 10.1038/nature02545. View

Yeo M, Lin P, Dahmus M, Gill G . A novel RNA polymerase II C-terminal domain phosphatase that preferentially dephosphorylates serine 5. J Biol Chem. 2003; 278(28):26078-85. DOI: 10.1074/jbc.M301791200. View

Ooi L, Wood I . Chromatin crosstalk in development and disease: lessons from REST. Nat Rev Genet. 2007; 8(7):544-54. DOI: 10.1038/nrg2100. View

Knockaert M, Sapkota G, Alarcon C, Massague J, Brivanlou A . Unique players in the BMP pathway: small C-terminal domain phosphatases dephosphorylate Smad1 to attenuate BMP signaling. Proc Natl Acad Sci U S A. 2006; 103(32):11940-5. PMC: 1567677. DOI: 10.1073/pnas.0605133103. View

Zavadil J, Bottinger E . TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 2005; 24(37):5764-74. DOI: 10.1038/sj.onc.1208927. View

10.

Oft M, Akhurst R, Balmain A . Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol. 2002; 4(7):487-94. DOI: 10.1038/ncb807. View

11.

Blanco M, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J . Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene. 2002; 21(20):3241-6. DOI: 10.1038/sj.onc.1205416. View

12.

Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J . The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000; 2(2):84-9. DOI: 10.1038/35000034. View

13.

Feng X, Derynck R . Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005; 21:659-93. DOI: 10.1146/annurev.cellbio.21.022404.142018. View

14.

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

15.

Junghans D, Haas I, Kemler R . Mammalian cadherins and protocadherins: about cell death, synapses and processing. Curr Opin Cell Biol. 2005; 17(5):446-52. DOI: 10.1016/j.ceb.2005.08.008. View

16.

Peinado H, Ballestar E, Esteller M, Cano A . Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol. 2003; 24(1):306-19. PMC: 303344. DOI: 10.1128/MCB.24.1.306-319.2004. View

17.

Vega S, Morales A, Ocana O, Valdes F, Fabregat I, Nieto M . Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004; 18(10):1131-43. PMC: 415638. DOI: 10.1101/gad.294104. View

18.

Zavadil J, Cermak L, Soto-Nieves N, Bottinger E . Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J. 2004; 23(5):1155-65. PMC: 380966. DOI: 10.1038/sj.emboj.7600069. View

19.

Taylor K, Hiscox S, Nicholson R . Zinc transporter LIV-1: a link between cellular development and cancer progression. Trends Endocrinol Metab. 2004; 15(10):461-3. DOI: 10.1016/j.tem.2004.10.003. View

20.

Cheng C, Wu P, Yu J, Huang C, Yue C, Wu C . Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene. Oncogene. 2001; 20(29):3814-23. DOI: 10.1038/sj.onc.1204505. View