Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2

Yasuhiro Mitsuuchi, Steven W. Johnson, Gonosuke Sonoda, Satosh Tanno, Erica A. Golemis, Joseph R. Testa

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

Abstract

AKT2 is a serine/threonine kinase implicated in human ovarian and pancreatic cancers. AKT2 is activated by a variety of growth factors and insulin via phosphatidylinositol 3-kinase (PI3K). However, its normal cellular role is not well understood. To gain insight into the function of AKT2, we performed yeast two-hybrid system to screen for interacting proteins. Using this technique, we identified a novel interactor, designated APPL, which contains a pleckstrin homology (PH) domain, a phosphotyrosine binding (PTB) domain and a leucine zipper, classes of motifs defined in signaling molecules as functional interaction domains with specific targets. The PH domain of APPL shows similarity to those found in GTPase-activating proteins such as oligophrenin-1 and Graf, whereas its PTB domain exhibits homology with CED-6, an adaptor protein that promotes engulfment of apoptotic cells, and IB1, a transactivator of the GLUT2 gene. APPL is highly expressed in skeletal muscle, heart, ovary and pancreas, tissues in which AKT2 mRNA is abundant. APPL interacts with the inactive form of AKT2; moreover, APPL binds to the PI3K catalytic subunit, p110α. These data suggest that APPL is an adaptor that may tether inactive AKT2 to p110α in the cytoplasm and thereby may expedite recruitment of AKT2 and p110α to the cell membrane upon mitogenic stimulation. Furthermore, the APPL gene was mapped to human chromosome 3p14.3-p21.1, where deletions and other rearrangements have often been reported in a variety of tumor types. The identification of APPL may facilitate further analysis of the physiological and oncogenic activities of AKT2.

Original languageEnglish
Pages (from-to)4891-4898
Number of pages8
JournalOncogene
Volume18
Issue number35
DOIs
StatePublished - Sep 2 1999

Keywords

  • Amino Acid Sequence
  • Binding Sites
  • Carrier Proteins/chemistry
  • Chromosomes, Human, Pair 3/genetics
  • Cloning, Molecular
  • Enzyme Activation
  • Female
  • Humans
  • Leucine Zippers
  • Molecular Sequence Data
  • Ovarian Neoplasms
  • Phosphatidylinositol 3-Kinases/chemistry
  • Phosphotyrosine/metabolism
  • Physical Chromosome Mapping
  • Precipitin Tests
  • Protein Serine-Threonine Kinases/genetics
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins/genetics
  • RNA, Messenger/analysis
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Tumor Cells, Cultured
  • Yeasts/genetics

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