Atlas of Genetics and Cytogenetics in Oncology and Haematology
PEBP1 (phosphatidylethanolamine binding protein 1)
| Identity |
| Other names | HCNP |
| HCNPpp | |
| PBP | |
| PEBP | |
| PEBP-1 | |
| RKIP | |
| HGNC | PEBP1 |
| Location | 12q24.23 |
| Location_base_pair | Starts at 117058253 and ends at 117067773 bp from pter (hg18-Mar_2006). |
| DNA/RNA |
 | |
| Diagram of the RKIP gene. Exons are depicted as filled boxes and untranslated regions are unfilled boxes. Introns are represented as lines between exons. Intron, exon, and untranslated region sizes are described in base pairs. | |
| Description | The gene is composed of 4 exons spanning a region of 9,520 base pairs. |
| Transcription | The mRNA contains 1507 nucleotides. Alternative splicing has not been described. In prostate cancer cell lines RKIP transcription is repressed by Snail through an E-box in its promoter. Promoter methylation does not seem to cause loss of RKIP expression. |
| Pseudogene | RKIP has two putative pseudogenes located on chromosomes 2 and 14. These are intronless sequences with no verified expression to date. |
| Protein |
 | |
| Stereo view of the human RKIP structure prepared with Pymol (Delano, 2002). Pocket residues H86 (left), H118 (right), D70 (top) and Y120 (bottom) are indicated. | |
| Description | RKIP is an 187 amino acid protein with a molecular mass of 21-23 kDa. The crystal structures of human, bovine and plant PEBPs are solved revealing no homologies to domains of known functions. The structure of RKIP features a b-fold formed by two anti-parallel b-sheets, a small C-terminal aba element, and a cavity at the surface, which could accommodate a small anion such as a phosphoryl group (see diagram above). Amino acids forming this cavity are conserved among all PEBP family members and constitute the PEB motif. |
| Expression | RKIP and its mammalian homologs are widely expressed in tissues; it has been detected in lung, oviduct and ovary, mammary glands, uterus, prostate epithelium, thyroid, mesenteric lymph node, megakaryocytes of the heart; spleen, liver, and epididymis, testis, spermatids, Leydig cells, steroidogenic cells of the adrenal gland zona fasiculata, small intestine, plasma cells, and neural cells such as brain oliodendricytes, Schwann cells, and Pukinje cells. |
| Localisation | RKIP is localized in the cytoplasm and at the plasma membrane. |
| Function | RKIP inhibits the Raf/MEK/ERK cascade. Identified as a Raf-1 interacting protein in a yeast two-hybrid screen, RKIP was found to inhibit phosphorylation and activation of MEK by Raf-1. RKIP inhibits the phosphorylation of the N-region of Raf-1 by (21-activated kinase) Pak and Src family kinases thereby inhibiting activation of Raf-1. PKC phosphorylation of RKIP following GPCR stimulation causes its release from Raf-1. Classical and atypical PKCs can phosphorylate RKIP at serine 153 causing dissociation of the Raf-1 kinase domain and RKIP, indicating that PKC can mediate ERK activation through RKIP. Once free from Raf-1, RKIP was shown to bind GRK-2 and block its activity, promoting and enhancing G protein signaling and MEK/ERK signaling. RKIP appears to support macrophage differentiation via inhibition of the NFKB pathway. RKIP inhibits the NF-kappaB pathway through interaction with NIK, TAK1, and IKK. RKIP was a novel effector of apoptosis signaling; this may occur by modulation of the NF-kappaB pathway and/or the regulation of the spindle checkpoint via Aurora B kinase and the spindle checkpoint by RKIP. RKIP regulation of Aurora kinase B and the spindle checkpoint through Raf-1/MEK/ERK signaling influences cell cycle fidelity. RKIP has serine protease activity. Purified RKIP was found to inhibit the serine proteases thrombin, chymotrypsin, and neuropsin. HCNP, the N-terminal fragment of RKIP, may play a role in phospholipid organization of the myelin sheath and septal cholinergic development of the hippocampus. HCNP can act on frog cardiac mechanical performance, exerting a negative inotropism. Results of these experiments suggest that RKIP/HCNP may be a new endocrine factor that regulates cardiac physiology. RKIP downregulation may be associated with the congenital heart disease manifested in Down syndrome. RKIP downregulation was found in the rat right ventricle and in the interventricular septum upon cardiac remodeling. RKIP has been found in the male reproductive tract with implications in the organization of sperm membranes during spermiogenesis. It has been identified as a decapacitation factor in mouse spermatozoa. RKIP and other proteins inhibited progesterone-induced acrosome reaction and zona pellucida binding of sperm. |
| Homology | No significant sequence homology to other proteins. Humans have two known family members, RKIP and PEBP4. RKIP has high sequence identity to mouse, rat, bovine, and monkey phosphatidylethanolamine binding proteins. |
| Implicated in |
| Entity | Breast cancer |
| Oncogenesis | Immunohistochemical examination of breast cancer lymph node metastases showed significant loss of RKIP protein expression compared to normal breast duct epithelia and primary tumors. There was a weak negative correlation between RKIP expression and apoptosis in breast tumors that did not have associated lymph node metastases. Low levels of RKIP may allow cancer cells to evade apoptosis. Breast cancer cell lines expressing low levels of RKIP undergo apoptosis following ectopic RKIP addition or Taxol treatment, which induced RKIP expression. |
| Entity | Prostate cancer |
| Prognosis | Decreased protein expression of RKIP may be a prognostic marker in prostate cancer, with low RKIP levels indicating early PSA failure. |
| Oncogenesis | Low levels of RKIP may protect cancer cells against apoptosis. Tumorgenic prostate cancer cell lines expressing low levels of RKIP increase their RKIP expression following treatment with a chemotherapeutic drug, sensitizing the cells to apoptosis. Cell lines with higher RKIP expression can be made resistant to apoptosis when RKIP is knocked down. RKIP is downregulated in prostate cancer progression and metastasis. Modulation of RKIP expression in prostate cancer cell lines changes invasive ability in vitro as well as development of metastases in vivo, with loss of RKIP corresponding to increased invasiveness and metastatic spread. MEK/ERK activation was associated with low or decreased RKIP expression in vitro, and vice-versa. RKIP mRNA can activate interferon-inducible 2š,5š-oligoadenylate synthetases (OAS), leading to RNase L activation. RNase L deficiency in prostate cancer cell lines (PC3, Du145, LNCap) is associated with resistance to apoptosis through OAS activation. |
| Entity | Melanoma |
| Note | RKIP mRNA and protein expression is reduced in melanoma cell lines versus normal melanocytes. AP-1 activation and ERK1/ERK2 phosphorylation decreased in Mel Im cells stably transfected with RKIP compared to control transfected cells. Immunohistochemical analyses showed reduced RKIP in primary melanoma versus normal normal skin, and further reduction in melanoma metastases. RKIP may act by inhibiting B-Raf kinase activity, as demonstrated in melanoma cell lines in vitro. |
| Entity | Hepatocellular carcinoma |
| Note | Hepatocellular carcinoma cell lines and HCC liver tissue showed decreased RKIP expression as compared to primary human hepatocytes or adjacent peritumoral tissues. Low RKIP expression was correlated with increased ERK activation and modulation of RKIP expression antagonized MAPK signaling in vitro. |
| Entity | Colorectal cancer |
| Note | Loss of RKIP, as studied in tissue microarrays of MMR-proficient and deficient colorectal cancer samples, was a marker of tumor progression and metastasis. Diminished RKIP expression was significantly positively associated with worse survival. |
| Entity | Insulinoma / Islet neoplasia |
| Note | Insulinomas showed decreased or absent RKIP expression as compared to normal nearby islets. ß-cell line HIT-TI5 proliferation, but not apoptotis, was inhibited by RKIP. |
| External links |
| Bibliography |
| Amino acid sequence of the Homo sapiens brain 21-23-kDa protein (neuropolypeptide h3), comparison with its counterparts from Rattus norvegicus and Bos taurus species, and expression of its mRNA in different tissues. |
| Seddiqi N, Bollengier F, Alliel PM, PŠrin JP, Bonnet F, Bucquoy S, JollŽs P, Schoentgen F |
| Journal of molecular evolution. 1994 ; 39 (6) : 655-660. |
| PMID 7807553 |
| Sequence analysis and immunolocalisation of phosphatidylethanolamine binding protein (PBP) in human brain tissue. |
| Moore C, Perry AC, Love S, Hall L |
| Brain research. Molecular brain research. 1996 ; 37 (1-2) : 74-78. |
| PMID 8738137 |
| Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. |
| Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C, Fee F, Katsanakis KD, Rose DW, Mischak H, Sedivy JM, Kolch W |
| Nature. 1999 ; 401 (6749) : 173-177. |
| PMID 10490027 |
| Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. |
| Kolch W |
| The Biochemical journal. 2000 ; 351 Pt 2 : 289-305. |
| PMID 11023813 |
| Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. |
| Yeung K, Janosch P, McFerran B, Rose DW, Mischak H, Sedivy JM, Kolch W |
| Molecular and cellular biology. 2000 ; 20 (9) : 3079-3085. |
| PMID 10757792 |
| The phosphatidylethanolamine-binding protein is the prototype of a novel family of serine protease inhibitors. |
| Hengst U, Albrecht H, Hess D, Monard D |
| The Journal of biological chemistry. 2001 ; 276 (1) : 535-540. |
| PMID 11034991 |
| Human phosphatidylethanolamine-binding protein facilitates heterotrimeric G protein-dependent signaling. |
| Kroslak T, Koch T, Kahl E, Hllt V |
| The Journal of biological chemistry. 2001 ; 276 (43) : 39772-39778. |
| PMID 11514577 |
| Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation. |
| Yeung KC, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, McFerran B, Wyche J, Kolch W, Sedivy JM |
| Molecular and cellular biology. 2001 ; 21 (21) : 7207-7217. |
| PMID 11585904 |
| The crystal structure of PEBP-2, a homologue of the PEBP/RKIP family. |
| Simister PC, Banfield MJ, Brady RL |
| Acta crystallographica. Section D, Biological crystallography. 2002 ; 58 (Pt 6 Pt 2) : 1077-1080. |
| PMID 12037323 |
| Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein. |
| Corbit KC, Trakul N, Eves EM, Diaz B, Marshall M, Rosner MR |
| The Journal of biological chemistry. 2003 ; 278 (15) : 13061-13068. |
| PMID 12551925 |
| Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. |
| Fu Z, Smith PC, Zhang L, Rubin MA, Dunn RL, Yao Z, Keller ET |
| Journal of the National Cancer Institute. 2003 ; 95 (12) : 878-889. |
| PMID 12813171 |
| Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. |
| Lorenz K, Lohse MJ, Quitterer U |
| Nature. 2003 ; 426 (6966) : 574-579. |
| PMID 14654844 |
| RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. |
| Chatterjee D, Bai Y, Wang Z, Beach S, Mott S, Roy R, Braastad C, Sun Y, Mukhopadhyay A, Aggarwal BB, Darnowski J, Pantazis P, Wyche J, Fu Z, Kitagwa Y, Keller ET, Sedivy JM, Yeung KC |
| The Journal of biological chemistry. 2004 ; 279 (17) : 17515-17523. |
| PMID 14766752 |
| Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin's lymphoma B cells by Rituximab. |
| Jazirehi AR, Vega MI, Chatterjee D, Goodglick L, Bonavida B |
| Cancer research. 2004 ; 64 (19) : 7117-7126. |
| PMID 15466208 |
| The role of Raf kinase inhibitor protein (RKIP) in health and disease. |
| Keller ET, Fu Z, Brennan M |
| Biochemical pharmacology. 2004 ; 68 (6) : 1049-1053. |
| PMID 15313400 |
| Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene. |
| Keller ET, Fu Z, Yeung K, Brennan M |
| Cancer letters. 2004 ; 207 (2) : 131-137. |
| PMID 15151133 |
| Raf-1 kinase inhibitor protein: structure, function, regulation of cell signaling, and pivotal role in apoptosis. |
| Odabaei G, Chatterjee D, Jazirehi AR, Goodglick L, Yeung K, Bonavida B |
| Advances in cancer research. 2004 ; 91 : 169-200. |
| PMID 15327891 |
| Reduction in Raf kinase inhibitor protein expression is associated with increased Ras-extracellular signal-regulated kinase signaling in melanoma cell lines. |
| Schuierer MM, Bataille F, Hagan S, Kolch W, Bosserhoff AK |
| Cancer research. 2004 ; 64 (15) : 5186-5192. |
| PMID 15289323 |
| Differentiation induction of human keratinocytes by phosphatidylethanolamine-binding protein. |
| Yamazaki T, Nakano H, Hayakari M, Tanaka M, Mayama J, Tsuchida S |
| The Journal of biological chemistry. 2004 ; 279 (31) : 32191-32195. |
| PMID 15155742 |
| Raf kinase inhibitory protein inhibits beta-cell proliferation. |
| Zhang L, Fu Z, Binkley C, Giordano T, Burant CF, Logsdon CD, Simeone DM |
| Surgery. 2004 ; 136 (3) : 708-715. |
| PMID 15349122 |
| Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis. |
| Hagan S, Al-Mulla F, Mallon E, Oien K, Ferrier R, Gusterson B, Garca JJ, Kolch W |
| Clinical cancer research : an official journal of the American Association for Cancer Research. 2005 ; 11 (20) : 7392-7397. |
| PMID 16243812 |
| The biology of a prostate cancer metastasis suppressor protein: Raf kinase inhibitor protein. |
| Keller ET, Fu Z, Brennan M |
| Journal of cellular biochemistry. 2005 ; 94 (2) : 273-278. |
| PMID 15565643 |
| RKIP downregulates B-Raf kinase activity in melanoma cancer cells. |
| Park S, Yeung ML, Beach S, Shields JM, Yeung KC |
| Oncogene. 2005 ; 24 (21) : 3535-3540. |
| PMID 15782137 |
| Raf kinase inhibitory protein regulates Raf-1 but not B-Raf kinase activation. |
| Trakul N, Menard RE, Schade GR, Qian Z, Rosner MR |
| The Journal of biological chemistry. 2005 ; 280 (26) : 24931-24940. |
| PMID 15886202 |
| Identification and characterization of PEBP as a calpain substrate. |
| Chen Q, Wang S, Thompson SN, Hall ED, Guttmann RP |
| Journal of neurochemistry. 2006 ; 99 (4) : 1133-1141. |
| PMID 17018026 |
| Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. |
| Eves EM, Shapiro P, Naik K, Klein UR, Trakul N, Rosner MR |
| Molecular cell. 2006 ; 23 (4) : 561-574. |
| PMID 16916643 |
| Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer. |
| Fu Z, Kitagawa Y, Shen R, Shah R, Mehra R, Rhodes D, Keller PJ, Mizokami A, Dunn R, Chinnaiyan AM, Yao Z, Keller ET |
| The Prostate. 2006 ; 66 (3) : 248-256. |
| PMID 16175585 |
| Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. |
| Lee HC, Tian B, Sedivy JM, Wands JR, Kim M |
| Gastroenterology. 2006 ; 131 (4) : 1208-1217. |
| PMID 17030190 |
| Selection and cloning of poly(rC)-binding protein 2 and Raf kinase inhibitor protein RNA activators of 2',5'-oligoadenylate synthetase from prostate cancer cells. |
| Molinaro RJ, Jha BK, Malathi K, Varambally S, Chinnaiyan AM, Silverman RH |
| Nucleic acids research. 2006 ; 34 (22) : 6684-6695. |
| PMID 17145707 |
| Regulation of RKIP binding to the N-region of the Raf-1 kinase. |
| Park S, Rath O, Beach S, Xiang X, Kelly SM, Luo Z, Kolch W, Yeung KC |
| FEBS letters. 2006 ; 580 (27) : 6405-6412. |
| PMID 17097642 |
| Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. |
| Beach S, Tang H, Park S, Dhillon AS, Keller ET, Kolch W, Yeung KC |
| Oncogene. 2008 ; 27 (15) : 2243-2248. |
| PMID 17952120 |
| Cross-regulation of VPAC(2) receptor desensitization by M(3) receptors via PKC-mediated phosphorylation of RKIP and inhibition of GRK2. |
| Huang J, Mahavadi S, Sriwai W, Grider JR, Murthy KS |
| American journal of physiology. Gastrointestinal and liver physiology. 2007 ; 292 (3) : G867-G874. |
| PMID 17170028 |
| Loss of raf-1 kinase inhibitor protein expression is associated with tumor progression and metastasis in colorectal cancer. |
| Minoo P, Zlobec I, Baker K, Tornillo L, Terracciano L, Jass JR, Lugli A |
| American journal of clinical pathology. 2007 ; 127 (5) : 820-827. |
| PMID 17439843 |
| MAP kinase meets mitosis: a role for Raf Kinase Inhibitory Protein in spindle checkpoint regulation. |
| Rosner MR |
| Cell division. 2007 ; 2 : page 1. |
| PMID 17214889 |
| Raf kinase inhibitory protein knockout mice: expression in the brain and olfaction deficit. |
| Theroux S, Pereira M, Casten KS, Burwell RD, Yeung KC, Sedivy JM, Klysik J |
| Brain research bulletin. 2007 ; 71 (6) : 559-567. |
| PMID 17292798 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 11-2007 | Sandy Beach, Kam C Yeung |
| Department of Cancer Biology and Biochemistry, College of Medicine, University of Toledo, Health Science Campus-(formerly Medical University of Ohio), 3035 Arlington Ave., Toledo, OH 43614, USA |
| Citation |
| This paper should be referenced as such : |
| Beach S, Yeung KC . PEBP1 (phosphatidylethanolamine binding protein 1). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PEBP1ID44021ch12q24.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Sat Oct 11 12:55:13 2008 |
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