Death-associated protein 4 binds MST1 and augments MST1-induced apoptosis

Yenshou Lin, Andrei Khokhlatchev, Daniel Figeys, Joseph Avruch

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Abstract

The protein kinase MST1 is proapoptotic when overexpressed in an active form, however, its physiologic regulation and cellular targets are unknown. An overexpressed inactive MST1 mutant associates in COS-7 cells with an endogenous 761-amino acid polypeptide known as "death-associated protein 4" (DAP4). The DAPs are a functionally heterogeneous array of polypeptides previously isolated by Kimchi and colleagues (Kimchi, A. (1998) Biochim. Biophys. Acta 1377, F13-F33 in a screen for elements involved in the interferon γ-induced apoptosis of HeLa cells. DAP4, which is encoded by a member of a vertebrate-only gene family, contains no identifiable domains, but is identical over its amino-terminal 488 amino acids to p52rIPK, a putative modulator of protein kinase R. DAP4 is a widely expressed, constitutively nuclear polypeptide that homodimerizes through its amino terminus and binds MST1 through its carboxyl-terminal segment. MST1 is predominantly cytoplasmic, but cycles continuously through the nucleus, as evidenced by its rapid accumulation in the nucleus after addition of the Crml inhibitor, leptomycin B. Overexpression of DAP4 does not cause apoptosis, however, coexpression of DAP4 with a submaximal amount of MST1 enhances MST1-Induced apoptosis in a dose-dependent fashion. DAP4 is not significantly phosphorylated by MST1 nor does it alter MST1 kinase activity in vivo or in vitro. MST1-induced apoptosis is suppressed by a dominant interfering mutant of p53. MST1 is unable to directly phosphorylate p53, however, DAP4 binds endogenous and recombinant p53. DAP4 may promote MST1-induced apoptosis by enabling colocalization of MST with p53.

Original languageEnglish
Pages (from-to)47991-48001
Number of pages11
JournalJournal of Biological Chemistry
Volume277
Issue number50
DOIs
Publication statusPublished - 2002 Dec 13

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Apoptosis
Proteins
Peptides
Death-Associated Protein Kinases
Amino Acids
COS Cells
HeLa Cells
Protein Kinases
Interferons
Vertebrates
Phosphotransferases
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Death-associated protein 4 binds MST1 and augments MST1-induced apoptosis. / Lin, Yenshou; Khokhlatchev, Andrei; Figeys, Daniel; Avruch, Joseph.

In: Journal of Biological Chemistry, Vol. 277, No. 50, 13.12.2002, p. 47991-48001.

Research output: Contribution to journalArticle

Lin, Yenshou ; Khokhlatchev, Andrei ; Figeys, Daniel ; Avruch, Joseph. / Death-associated protein 4 binds MST1 and augments MST1-induced apoptosis. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 50. pp. 47991-48001.
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