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Addition of N-terminal peptide sequences activates the oncogenic and signaling potentials of the catalytic subunit p110α of phosphoinositide-3-kinase

Academic Article
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Overview

authors

  • Sun, M. H.
  • Hart, J. R.
  • Hillmann, P.
  • Gymnopoulos, M.
  • Vogt, Peter K.

publication date

  • November 2011

journal

  • Cell Cycle  Journal

abstract

  • Addition of short (6 to 16 amino acids) peptide sequences to the N-terminus of p110? induces a gain of function. Such sequences include the common Flag, His, and VSV tags as well as random sequences. An N-terminal myristylation signal generally believed to activate p110? by providing a constitutive membrane address is also activating, if myristylation is mutationally abolished. The gain of function seen with N-terminally tagged (NTT) p110? constructs extends to signaling, oncogenic transformation and stimulation of cell growth. The activating effect of N-terminal tags requires a functional Ras-binding domain in p110?. Mutations in that domain (T208D and K227A) abolish the gains of function in oncogenicity and signaling. The dominant negative mutant of Ras, RasN17, interferes with transformation induced by NTT p110?. In contrast, binding to p85 activity is not required for cellular transformation and enhanced signaling by NTT p110?.
  • Addition of short (6 to 16 amino acids) peptide sequences to the N-terminus of p110α induces a gain of function. Such sequences include the common Flag, His, and VSV tags as well as random sequences. An N-terminal myristylation signal generally believed to activate p110α by providing a constitutive membrane address is also activating, if myristylation is mutationally abolished. The gain of function seen with N-terminally tagged (NTT) p110α constructs extends to signaling, oncogenic transformation and stimulation of cell growth. The activating effect of N-terminal tags requires a functional Ras-binding domain in p110α. Mutations in that domain (T208D and K227A) abolish the gains of function in oncogenicity and signaling. The dominant negative mutant of Ras, RasN17, interferes with transformation induced by NTT p110α. In contrast, binding to p85 activity is not required for cellular transformation and enhanced signaling by NTT p110α.

subject areas

  • Amino Acid Sequence
  • Animals
  • Catalytic Domain
  • Cell Transformation, Neoplastic
  • Chick Embryo
  • Class Ia Phosphatidylinositol 3-Kinase
  • HEK293 Cells
  • Humans
  • Mutagenesis, Site-Directed
  • Protein Structure, Tertiary
  • Protein Subunits
  • Signal Transduction
  • ras Proteins
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Research

keywords

  • N-terminal tags
  • Ras binding domain
  • oncogenicity
  • p110 alpha
  • p85 binding mutations
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Identity

PubMed Central ID

  • PMC3266008

International Standard Serial Number (ISSN)

  • 1538-4101

Digital Object Identifier (DOI)

  • 10.4161/cc.10.21.17920

PubMed ID

  • 22045127
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Additional Document Info

start page

  • 3731

end page

  • 3739

volume

  • 10

issue

  • 21

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