Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Lucia Mendoza-Viveros
  • Hai-Ying Mary ChengEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101762


Historical Background

Phosphatidylethanolamine-binding protein 1 (PEBP-1) was first isolated as a cytosolic, 23 kDa protein from bovine brain and was also found in soluble extracts from human platelets and rodent brains (Bernier and Jolles 1984). A series of studies over the next decade led to its identification as the precursor for hippocampal cholinergic neurostimulating peptide (HCNP), an acetylated eleven amino acid long peptide conserved in the rat, human, and bovine genome (Tohdoh et al. 1995). Although, it was originally named for its binding affinity for the phospholipid phosphatidylethanolamine, a breakthrough report characterized PEBP-1 as a Raf-1 kinase binding protein with the ability to inhibit the mitogen-activated protein kinase (MAPK) pathway;...

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  1. Al-Mulla F, Bitar MS, Al-Maghrebi M, Behbehani AI, Al-Ali W, Rath O, et al. Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β. Cancer Res. 2011a;71(4):1334–43.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Al-Mulla F, Bitar MS, Taqi Z, Rath O, Kolch W. RAF kinase inhibitory protein (RKIP) modulates cell cycle kinetics and motility. Mol Biosyst. 2011b;7:928–41.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Antoun G, Bouchard-Cannon P, Cheng H-YM. Regulation of MAPK/ERK signaling and photic entrainment of the suprachiasmatic nucleus circadian clock by raf kinase inhibitor protein. J Neurosci. 2012;32(14):4867–77.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bernier I, Jolles P. Purification and characterization of a basic 23 kDa cytosolic protein from bovine brain. Biochim Biophys Acta (BBA)/Protein Struct Mol. 1984;790(2):174–81.CrossRefGoogle Scholar
  5. Deiss K, Kisker C, Lohse MJ, Lorenz K. Raf kinase inhibitor protein (RKIP) dimer formation controls its target switch from Raf1 to G protein-coupled receptor kinase (GRK) 2. J Biol Chem. 2012;287(28):23407–17.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Frayne J, Ingram C, Love S, Hall L. Localisation of phosphatidylethanolamine-binding protein in the brain and other tissues of the rat. Cell Tissue Res. 1999;298(3):415–23.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Fu Z, Kitagawa Y, Shen R, Shah R, Mehra R, Rhodes D, et al. Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer. Prostate. 2006;66(3):248–56.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Han NK, Kim BC, Lee HC, Lee YJ, Park MJ, Chi SG, et al. Secretome analysis of ionizing radiation-induced senescent cancer cells reveals that secreted RKIP plays a critical role in neighboring cell migration. Proteomics. 2012;12(18):2822–32.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Hellmann J, Rommelspacher H, Mühlbauer E, Wernicke C. Raf kinase inhibitor protein enhances neuronal differentiation in human SH-SY5Y cells. Dev Neurosci. 2010;32(1):33–46.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Lamiman K, Keller JM, Mizokami A, Zhang J, Keller ET. Survey of Raf kinase inhibitor protein (RKIP) in multiple cancer types. Crit Rev Oncog. 2014;19(6):455–68.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Lee S-J, Lee S-H, Yoon M-H, Park B-J. A new p53 target gene, RKIP, is essential for DNA damage-induced cellular senescence and suppression of ERK activation. Neoplasia. 2013;15(7):727–37.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Li D, Cai H, Wang X, Feng Y, Cai S. Promoter methylation of Raf kinase inhibitory protein: a significant prognostic indicator for patients with gastric adenocarcinoma. Exp Ther Med. 2014;8(3):844–50.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Lorenz K, Lohse MJ, Quitterer U. Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature. 2003;426(6966):574–9.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Matsukawa N, Furuya Y, Ogura H, Ojika K. HCNP precursor protein transgenic mice display a depressive-like phenotype in old age. Brain Res. 2010;1349:153–61.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Ohi Y, Kato D, Mizuno M, Sato T, Ueki Y, Borlongan CV, et al. Enhancement of long-term potentiation via muscarinic modulation in the hippocampus of HCNP precursor transgenic mice. Neurosci Lett. 2015;597:1–6.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Ojika K, Mitake S, Tohdoh N, Appel SH, Otsuka Y, Katada E, et al. Hippocampal cholinergic neurostimulating peptides (HCNP). Prog Neurobiol. 2000;60(1):37–83.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Okita K, Matsukawa N, Maki M, Nakazawa H, Katada E, Hattori M, et al. Analysis of DNA variations in promoter region of HCNP gene with Alzheimer’s disease. Biochem Biophys Res Commun. 2009;379(2):272–6.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Schmid E, Neef S, Berlin C, Tomasovic A, Kahlert K, Nordbeck P, et al. Cardiac RKIP induces a beneficial β-adrenoceptor-dependent positive inotropy. Nat Med. 2015;21(11):1298–306.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Skinner JJ, Rosner MR. RKIP structure drives its function: a three-state model for regulation of RKIP. Crit Rev Oncog. 2014;19(6):483–8.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Tavel L, Jaquillard L, Karsisiotis AI, Saab F, Jouvensal L, Brans A, et al. Ligand binding study of human PEBP1/RKIP: Interaction with nucleotides and raf-1 peptides evidenced by NMR and mass spectrometry. PLoS One. 2012;7(4):e36187.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Theroux S, Pereira M, Casten KS, Burwell RD, Yeung KC, Sedivy JM, et al. Raf kinase inhibitory protein knockout mice: expression in the brain and olfaction deficit. Brain Res Bull. 2007;71:559–67.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Tohdoh N, Tojo S, Agui H, Ojika K. Sequence homology of rat and human HCNP precursor proteins, bovine phosphatidylethanolamine-binding protein and rat 23-kDa protein associated with the opioid-binding protein. Brain Res Mol Brain Res. 1995;30(2):381–4.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):394.CrossRefGoogle Scholar
  24. Wright KT, AT V. RKIP contributes to IFN- synthesis by CD8+ T cells after serial TCR triggering in systemic inflammatory response syndrome. J Immunol. 2013;191:708–16.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Yamamoto Y, Lee D, Kim Y, Lee B, Seo C, Kawasaki H, et al. Raf kinase inhibitory protein is required for cerebellar long-term synaptic depression by mediating PKC-dependent MAPK activation. J Neurosci. 2012;32(41):14254–64.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Yesilkanal AE, Rosner MR. Raf kinase inhibitory protein (RKIP) as a metastasis suppressor: regulation of signaling networks in cancer. Crit Rev Oncog. 2014;19(6):447–54.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C, et al. Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature. 1999;401(6749):173–7.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Yeung K, Janosch P, McFerran B, Rose DW, Mischak H, Sedivy JM, et al. Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol Cell Biol. 2000;20(9):3079–85.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Yeung K, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, et al. Raf kinase inhibitor protein interacts with NF-κ B-inducing kinase and TAK1 and inhibits NF-κ B activation. Mol Cell Biol. 2001;21(21):7207–17.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Zebisch A, Wölfler A, Fried I, Wolf O, Lind K, Bodner C, et al. Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia. Leukemia. 2012;26(8):1842–9.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Zhu S, Mc Henry KT, Lane WS, Fenteany G. A chemical inhibitor reveals the role of Raf kinase inhibitor protein in cell migration. Chem Biol. 2005;12(9):981–91.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of BiologyUniversity of Toronto MississaugaMississaugaCanada
  2. 2.Department of Cell and Systems BiologyUniversity of TorontoTorontoCanada