P21-activated Kinase 1 Interacts with and Phosphorylates Histone H3 in Breast Cancer Cells

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2002 Aug 2

PMID 12151336

Citations 52

Authors

Feng Li

Liana Adam

Ratna K Vadlamudi

Hongyi Zhou

Subrata Sen

Jonathan Chernoff

Mahitosh Mandal

Rakesh Kumar

Affiliations

Soon will be listed here.

Abstract

Stimulation of p21-activated kinase-1 (Pak1) signaling promotes motility, invasiveness, anchorage-independent growth and abnormal mitotic assembly in human breast cancer cells. Here, we provide new evidence that, before the onset of mitosis, activated Pak1 is specifically localized with the chromosomes during prophase and on the centrosomes in metaphase and moves to the contraction ring during cytokinesis. To identify mitosis-specific substrates of Pak1, we screened a synchronized G2-M expression library by using a glutathione transferase Pak1 solid-phase-based kinase reaction. This analysis identified histone H3 as a substrate of Pak1 both in vitro and in vivo, and it specifically interacted with Pak1 but not Pak2 or Pak3. Site-directed mutagenesis indicated that Pak1 phosphorylates histone H3 on Ser10. Expressions of the wild-type, or catalytically active, Pak1 caused it to appear at the poles corresponding to mitotic centrosomes in a variety of mammalian cells. Together, these results suggest for the first time that Pak1 interacts with and phosphorylates histone H3 and may thus influence the Pak1-histone H3 pathway, which in turn may influence mitotic events in breast cancer cells.

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References

Cheung P, Allis C, Sassone-Corsi P . Signaling to chromatin through histone modifications. Cell. 2000; 103(2):263-71. DOI: 10.1016/s0092-8674(00)00118-5. View

de la Barre A, Gerson V, Gout S, Creaven M, Allis C, Dimitrov S . Core histone N-termini play an essential role in mitotic chromosome condensation. EMBO J. 2000; 19(3):379-91. PMC: 305575. DOI: 10.1093/emboj/19.3.379. View

Sells M, Pfaff A, Chernoff J . Temporal and spatial distribution of activated Pak1 in fibroblasts. J Cell Biol. 2001; 151(7):1449-58. PMC: 2150672. DOI: 10.1083/jcb.151.7.1449. View

Saffery R, Irvine D, Griffiths B, Kalitsis P, Choo K . Components of the human spindle checkpoint control mechanism localize specifically to the active centromere on dicentric chromosomes. Hum Genet. 2000; 107(4):376-84. DOI: 10.1007/s004390000386. View

Mazumdar A, Wang R, Mishra S, Adam L, Mandal M, Vadlamudi R . Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat Cell Biol. 2001; 3(1):30-7. DOI: 10.1038/35050532. View

Zeitlin S, Barber C, Allis C, Sullivan K, Sullivan K . Differential regulation of CENP-A and histone H3 phosphorylation in G2/M. J Cell Sci. 2001; 114(Pt 4):653-61. DOI: 10.1242/jcs.114.4.653. View

Adams R, CARMENA M, Earnshaw W . Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol. 2001; 11(2):49-54. DOI: 10.1016/s0962-8924(00)01880-8. View

Jenuwein T, Allis C . Translating the histone code. Science. 2001; 293(5532):1074-80. DOI: 10.1126/science.1063127. View

Steuer E, Wordeman L, Schroer T, Sheetz M . Localization of cytoplasmic dynein to mitotic spindles and kinetochores. Nature. 1990; 345(6272):266-8. DOI: 10.1038/345266a0. View

10.

Earnshaw W, Bernat R . Chromosomal passengers: toward an integrated view of mitosis. Chromosoma. 1991; 100(3):139-46. DOI: 10.1007/BF00337241. View

11.

Kumar R, Korutla L, Zhang K . Cell cycle-dependent modulation of alpha-interferon-inducible gene expression and activation of signaling components in Daudi cells. J Biol Chem. 1994; 269(41):25437-41. View

12.

Echeverri C, Paschal B, Vaughan K, Vallee R . Molecular characterization of the 50-kD subunit of dynactin reveals function for the complex in chromosome alignment and spindle organization during mitosis. J Cell Biol. 1996; 132(4):617-33. PMC: 2199864. DOI: 10.1083/jcb.132.4.617. View

13.

Manser E, Huang H, Loo T, Chen X, Dong J, Leung T . Expression of constitutively active alpha-PAK reveals effects of the kinase on actin and focal complexes. Mol Cell Biol. 1997; 17(3):1129-43. PMC: 231838. DOI: 10.1128/MCB.17.3.1129. View

14.

Sells M, Knaus U, Bagrodia S, Ambrose D, Bokoch G, Chernoff J . Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr Biol. 1997; 7(3):202-10. DOI: 10.1016/s0960-9822(97)70091-5. View

15.

Lu W, Katz S, Gupta R, Mayer B . Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck. Curr Biol. 1997; 7(2):85-94. DOI: 10.1016/s0960-9822(06)00052-2. View

16.

Fukunaga R, Hunter T . MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J. 1997; 16(8):1921-33. PMC: 1169795. DOI: 10.1093/emboj/16.8.1921. View

17.

Wolffe A, Kurumizaka H . The nucleosome: a powerful regulator of transcription. Prog Nucleic Acid Res Mol Biol. 1998; 61:379-422. DOI: 10.1016/s0079-6603(08)60832-6. View

18.

Daniels R, Bokoch G . p21-activated protein kinase: a crucial component of morphological signaling?. Trends Biochem Sci. 1999; 24(9):350-5. DOI: 10.1016/s0968-0004(99)01442-5. View

19.

Vadlamudi R, Adam L, Wang R, Mandal M, Nguyen D, Sahin A . Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J Biol Chem. 2000; 275(46):36238-44. DOI: 10.1074/jbc.M002138200. View