Disease relevance of PEBP1

• Loss of RKIP function promotes tumor metastasis in prostate cancer and melanoma [1].
• Loss of raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells [1].
• RKIP downregulates B-Raf kinase activity in melanoma cancer cells [2].
• RKIP has been shown to fit the criteria of being a metastasis suppressor gene, including having decreased expression in prostate cancer metastases and restoring RKIP expression in a prostate cancer cell line diminishes metastasis in a murine model [3].
• RKIP expression is independent of other markers for breast cancer progression and prognosis [4].
• Taken together, our results suggest that RKIP may be a NPC metastasis suppressor, and decreased RKIP expression is associated with the increased invasive capability of NPC cells possibly through the activation of Raf-1/MEK/ERK pathway [5].

Psychiatry related information on PEBP1

• In addition to its roles in physiology, dysregulated RKIP expression has the potential to contribute to pathophysiological processes including Alzheimer's disease and diabetic nephropathy [3].

High impact information on PEBP1

• Finally, RKIP depletion or Raf hyperactivation reduces kinetochore localization and kinase activity of Aurora B, a regulator of the spindle checkpoint [6].
• We now show that RKIP associates with centrosomes and kinetochores and regulates the spindle checkpoint in mammalian cells [6].
• RKIP depletion causes decreases in the mitotic index, the number of metaphase cells, and traversal times from nuclear envelope breakdown to anaphase, and an override of mitotic checkpoints induced by spindle poisons [6].
• Low RKIP levels were correlated with enhanced extracellular signal-regulated-kinase (ERK)/MAPK pathway activation [1].
• The underlying mechanisms of RKIP were assessed with immunoblot analysis, Raf kinase activity assay, cell proliferation, and migration assays after either overexpression or knockdown of RKIP expression in HCC cell lines [1].

Chemical compound and disease context of PEBP1

• Small interfering RNA targeted against B-Raf or a Raf kinase inhibitor (BAY 43-9006) was used to reduce expression and/or activity of (V599E)B-Raf in melanoma tumors [7].
• PBP 10, an antibacterial, cell membrane-permeant rhodamine B-conjugated peptide derived from the polyphosphoinositide binding site of gelsolin, interacts selectively with both lipopolysaccharides (LPS) and lipoteichoic acid (LTA), the distinct components of gram-negative and gram-positive bacteria, respectively [8].
• 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 [9].

Biological context of PEBP1

• Conclusions: Our findings indicate that down-regulation of RKIP expression is a major factor in activation of the IGF-I/ERK/MAPK pathway during human hepatocarcinogenesis [1].
• Overexpression of RKIP sensitizes tumor cells to chemotherapeutic drug-induced apoptosis [10].
• Genetic epistasis analysis involving the ectopic expression of kinases acting in the NF-kappaB pathway indicated that RKIP acts upstream of the kinase complex that mediates the phosphorylation and inactivation of the inhibitor of NF-kappaB (IkappaB) [11].
• RKIP is involved in neural development, cardiac function and spermatogenesis and appears to have serine protease activity [3].
• Differential gene expression analysis of human blood monocytes has identified the Raf kinase inhibitor protein (RKIP) as a continuously upregulated gene in macrophage and dendritic cell maturation [12].

Anatomical context of PEBP1

• These novel findings reveal a signaling pathway triggered by rituximab, whereby rituximab-mediated up-regulation of RKIP adversely regulates the activity of the ERK1/2 pathway, Bcl-(xL) expression, and subsequent chemosensitization of drug-refractory NHL B cells [13].
• However, in lymph node metastases, RKIP expression was highly significantly reduced or lost (P = 0.000003) [4].
• The expression and role of RKIP within the pancreas are unknown [14].
• RESULTS: RKIP was expressed only within pancreatic islet cells [14].
• Screening nine melanoma cell lines at mRNA and protein levels, we detected significant down-regulation of RKIP expression in comparison with normal melanocytes [15].

Associations of PEBP1 with chemical compounds

• A novel human phosphatidylethanolamine-binding protein resists tumor necrosis factor alpha-induced apoptosis by inhibiting mitogen-activated protein kinase pathway activation and phosphatidylethanolamine externalization [16].
• Our results indicate that the Raf kinase inhibitor BAY 43-9006 might also directly or indirectly interact with platinum transporter proteins in vitro [17].
• Although initially developed as a Raf kinase inhibitor, it can also target several other important tyrosine kinases including VEGFR-2, Flt-3, and c-Kit, which contributes to its antiproliferative and antiangiogenic properties [18].
• In a gel retardation assay the partially purified AR specifically recognizes an androgen response element of the rat prostatic binding protein gene [19].
• One of these is annotated as a glucose binding protein (GBP) based on its genetic linkage to genes that are homologous to an ATP-binding cassette glucose transport system, although the PBP sequence is homologous to periplasmic maltose binding proteins (MBPs) [20].

Physical interactions of PEBP1

• The phosphorylated RKIP binds to and inhibits G-protein-coupled receptor kinase, resulting in sustained G-protein signaling [3].
• Previous studies demonstrated that RKIP binds to Raf-1 and prevents the activation of the extracellular regulated kinase (ERK) cascade [21].

Enzymatic interactions of PEBP1

• RKIP was than identified as a protein that bound Raf and blocked its ability to phosphorylate MEK, thus earning its new name of RKIP [22].

Regulatory relationships of PEBP1

• Immunofluorescent double staining revealed that RKIP was expressed in most beta cells and a subset of pancreatic polypeptide-expressing cells [14].
• RKIP blocks Raf-induced phosphorylation of MEK [23].
• Finally, these results raise the possibility that RKIP status in tumors could influence the efficacy of treatments such as poisons that stimulate the Aurora B-dependent spindle assembly checkpoint [24].
• Subsequent to identification of its role in the Raf:MEK pathway, RKIP has been demonstrated to regulate several other signaling pathways including G-protein signaling and NF-kappaB signaling [22].
• These findings demonstrate that RKIP overexpression regulates tumor cell sensitivity to TRAIL via inhibition of YY1, up-regulation of DR5, and modulation of apoptotic pathways [25].

Other interactions of PEBP1

• We showed that the effects of RKIP on B-Raf functions were independent of its known inhibitory action on Raf-1 [2].
• Previous findings implicated a negative regulatory role of the Raf-1 kinase inhibitor protein (RKIP) on the ERK1/2 pathway [13].
• No significant correlations were observed between RKIP expression and histologic type, tumor differentiation grade, size, or estrogen receptor status [4].
• Remarkably, RKIP, which was shown to interfere with the activation of MEK by Raf, was highly expressed in primary as well as in metastatic MCC [26].
• Analytical solutions, relating the steady-state values of the fast varying protein concentrations and the slow varying ones, are derived and interpreted as restrictions on the regulatory role of RKIP on ERK-pathway [27].

Analytical, diagnostic and therapeutic context of PEBP1

• Methods: The levels of RKIP expression in HCC tumor and corresponding peritumoral tissues were determined by immunohistochemistry and Western blot analysis [1].
• Using realtime RT-PCR and Western blot analysis we were able to confirm the initial DNA-microarray findings of RKIP induction on mRNA and protein levels [12].
• Recently, RKIP has been recognized as a strong candidate for a metastasis suppressor gene in cell and animal model systems [4].
• It confirms the results of cell culture and animal studies, suggesting that in human breast cancer, RKIP is a metastasis suppressor gene whose expression must be down-regulated for metastases to develop [4].
• Co-localization of RKIP within islet cell subtypes was performed by using double immunofluorescence staining with antibodies directed toward RKIP and endocrine markers [14].

References