PEBP1 (phosphatidylethanolamine binding protein 1)

2007-11-01   Sandy Beach , Kam C Yeung 

Department of Cancer Biology, Biochemistry, College of Medicine, University of Toledo, Health Science Campus-(formerly Medical University of Ohio), 3035 Arlington Ave., Toledo, OH 43614, USA




Atlas Image
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.


The gene is composed of 4 exons spanning a region of 9,520 base pairs.


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.


RKIP has two putative pseudogenes located on chromosomes 2 and 14. These are intronless sequences with no verified expression to date.



RKIP belongs to a highly conserved family of phospholipid-binding proteins, which have been recognized and studied for several years as PEBP. These proteins are represented in eukaryotes, bacteria, and archae. One of the interesting properties of some PEBP family members is that they are cleaved at the N-terminus to release an undecapeptide which has been named hippocampal cholinergic neurostimulating peptide (HCNP).
Atlas Image
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.


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.


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.


RKIP is localized in the cytoplasm and at the plasma membrane.


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.


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 name
Breast cancer
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 name
Prostate cancer
Decreased protein expression of RKIP may be a prognostic marker in prostate cancer, with low RKIP levels indicating early PSA failure.
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 2,5-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 name
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 name
Hepatocellular carcinoma
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 name
Colorectal cancer
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 name
Insulinoma / Islet neoplasia
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.


Pubmed IDLast YearTitleAuthors
179521202008Snail is a repressor of RKIP transcription in metastatic prostate cancer cells.Beach S et al
147667522004RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis.Chatterjee D et al
170180262006Identification and characterization of PEBP as a calpain substrate.Chen Q et al
125519252003Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein.Corbit KC et al
169166432006Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint.Eves EM et al
161755852006Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer.Fu Z et al
128131712003Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis.Fu Z et al
162438122005Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis.Hagan S et al
110349912001The phosphatidylethanolamine-binding protein is the prototype of a novel family of serine protease inhibitors.Hengst U et al
171700282007Cross-regulation of VPAC(2) receptor desensitization by M(3) receptors via PKC-mediated phosphorylation of RKIP and inhibition of GRK2.Huang J et al
154662082004Inhibition 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 et al
155656432005The biology of a prostate cancer metastasis suppressor protein: Raf kinase inhibitor protein.Keller ET et al
110238132000Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions.Kolch W et al
115145772001Human phosphatidylethanolamine-binding protein facilitates heterotrimeric G protein-dependent signaling.Kroslak T et al
170301902006Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells.Lee HC et al
146548442003Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2.Lorenz K et al
174398432007Loss of raf-1 kinase inhibitor protein expression is associated with tumor progression and metastasis in colorectal cancer.Minoo P et al
171457072006Selection 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 et al
87381371996Sequence analysis and immunolocalisation of phosphatidylethanolamine binding protein (PBP) in human brain tissue.Moore C et al
153278912004Raf-1 kinase inhibitor protein: structure, function, regulation of cell signaling, and pivotal role in apoptosis.Odabaei G et al
170976422006Regulation of RKIP binding to the N-region of the Raf-1 kinase.Park S et al
157821372005RKIP downregulates B-Raf kinase activity in melanoma cancer cells.Park S et al
172148892007MAP kinase meets mitosis: a role for Raf Kinase Inhibitory Protein in spindle checkpoint regulation.Rosner MR et al
152893232004Reduction in Raf kinase inhibitor protein expression is associated with increased Ras-extracellular signal-regulated kinase signaling in melanoma cell lines.Schuierer MM et al
78075531994Amino 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 et al
120373232002The crystal structure of PEBP-2, a homologue of the PEBP/RKIP family.Simister PC et al
172927982007Raf kinase inhibitory protein knockout mice: expression in the brain and olfaction deficit.Theroux S et al
158862022005Raf kinase inhibitory protein regulates Raf-1 but not B-Raf kinase activation.Trakul N et al
151557422004Differentiation induction of human keratinocytes by phosphatidylethanolamine-binding protein.Yamazaki T et al
107577922000Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein.Yeung K et al
104900271999Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP.Yeung K et al
115859042001Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation.Yeung KC et al
153491222004Raf kinase inhibitory protein inhibits beta-cell proliferation.Zhang L et al

Other Information

Locus ID:

NCBI: 5037
MIM: 604591
HGNC: 8630
Ensembl: ENSG00000089220


dbSNP: 5037
ClinVar: 5037
TCGA: ENSG00000089220


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Diseases of signal transductionREACTOMER-HSA-5663202
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
MAP2K and MAPK activationREACTOMER-HSA-5674135
Negative regulation of MAPK pathwayREACTOMER-HSA-5675221
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
RET signalingREACTOMER-HSA-8853659
Oncogenic MAPK signalingREACTOMER-HSA-6802957
Signaling by RAS mutantsREACTOMER-HSA-6802949
Signaling by high-kinase activity BRAF mutantsREACTOMER-HSA-6802948
Signaling by moderate kinase activity BRAF mutantsREACTOMER-HSA-6802946
Paradoxical activation of RAF signaling by kinase inactive BRAFREACTOMER-HSA-6802955
Signaling by BRAF and RAF fusionsREACTOMER-HSA-6802952

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
191536032009Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7.150
146548442003Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2.113
225056482012Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer.81
290539692017PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals.73
218739752011Signalling pathway for RKIP and Let-7 regulates and predicts metastatic breast cancer.72
162438122005Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis.71
147667522004RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis.65
171791022006Raf kinase inhibitor protein expression in a survival analysis of colorectal cancer patients.65
179521202008Snail is a repressor of RKIP transcription in metastatic prostate cancer cells.61
169166432006Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint.60


Sandy Beach ; Kam C Yeung

PEBP1 (phosphatidylethanolamine binding protein 1)

Atlas Genet Cytogenet Oncol Haematol. 2007-11-01

Online version: