PAPA-1 Is a nuclear binding partner of IGFBP-2 and modulates its growth-promoting actions

Mol Endocrinol. 2009 Feb;23(2):169-75. doi: 10.1210/me.2008-0168. Epub 2008 Dec 18.


IGF-binding proteins (IGFBPs) have multiple cellular effects, which occur by both IGF-dependent and -independent mechanisms. IGFBP-2 is involved in the regulation of both normal and carcinogenic cell growth. To further understand the actions of IGFBP-2, we carried out a yeast two-hybrid screen to search for intracellular partner proteins using a human prostate cDNA library. We isolated Pim-1-associated protein-1 (PAP-1)-associated protein-1 (PAPA-1) as an IGFBP-2-binding protein, whose expression and subcellular localization is regulated by both IGFBP-2 and androgens. Coimmunoprecipitation and glutathione S-transferase pull-down assay confirmed the interaction in vitro, and confocal microscopy showed the colocalization of IGFBP-2 and PAPA-1 in the nucleus. Suppression of PAPA-1 by small interfering RNA treatment enhanced the growth-promoting effect of IGFBP-2. Conversely, IGFBP-2-promoted bromodeoxyuridine incorporation into LNCaP cells was abrogated by the simultaneous overexpression of myc-hPAPA-1. Mouse embryonic fibroblasts from IGFBP-2 knockout mouse showed diminished growth activity compared with wild type, and expression of FLAG-mPAPA-1 decreased cell proliferation in IGFBP-2 knockout, but not control mouse embryonic fibroblasts. These studies suggest that the growth-promoting role of IGFBP-2 in prostate cancer is inhibited by its intracellular interaction with PAPA-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Insulin-Like Growth Factor Binding Protein 2 / genetics
  • Insulin-Like Growth Factor Binding Protein 2 / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Pancreatitis-Associated Proteins
  • Prostate / metabolism
  • Prostatic Neoplasms / metabolism
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Proto-Oncogene Proteins c-pim-1 / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Two-Hybrid System Techniques


  • Carrier Proteins
  • Cell Cycle Proteins
  • INO80B protein, human
  • Insulin-Like Growth Factor Binding Protein 2
  • Nuclear Proteins
  • PAPA-1 protein, mouse
  • Pancreatitis-Associated Proteins
  • REG3A protein, human
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-pim-1