Raf kinase inhibitory protein: a signal transduction modulator and metastasis suppressor

Granovsky, Alexey E.; Rosner, Marsha Rich

doi:10.1038/cr.2008.43

Cited by 144 publications

(128 citation statements)

References 51 publications

(54 reference statements)

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“…In cancer, RKIP is considered to be a signal transduction modulator and a metastasis suppressor (14), and down regulated in several human tumors, mainly in highly metastatic carcinomas (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Noteworthy, RKIP has been shown to be a prognostic marker in prostate cancer, colorectal carcinomas, gliomas and GISTs (25,(27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients

et al. 2012

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Abstract. Gastric cancer is a leading cause of cancer-related mortality, and the presence of lymph node metastasis an important prognostic factor. Downregulation of RKIP has been associated with tumor progression and metastasis in several types of neoplasms, being currently categorized as a metastasis suppressor gene. Our aim was to determine the expression levels of RKIP in gastric tissues and to evaluate its impact in the clinical outcome of gastric carcinoma patients. RKIP expression levels were studied by immunohistochemistry in a series of gastric tissues. Overall, we analysed 222 non-neoplastic gastric tissues, 152 primary tumors and 42 lymph node metastasis samples. We observed that RKIP was highly expressed in ~83% of non-neoplastic tissues (including normal tissue and metaplasia), was lost in ~56% of primary tumors and in ~90% of lymph node metastasis samples. Loss of RKIP expression was significantly associated with several markers of poor clinical outcome, including the presence of lymph node metastasis. Furthermore, the absence of RKIP protein constitutes an independent prognostic marker for these patients. In conclusion, RKIP expression is significantly lost during gastric carcinoma progression being almost absent in lymph node metastasis samples. Of note, we showed that the absence of RKIP expression is associated with poor outcome features of gastric cancer patients, this being also an independent prognostic marker.

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Section: Introductionmentioning

confidence: 99%

Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients

et al. 2012

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“…On the other hand, Raf kinase inhibitory protein (RKIP), a member of the phosphatidylethanolamine-binding protein family, has proved to be a significant molecule in suppressing cancer metastasis [15]. It is an evolutionarily conserved small protein, and was originally identified as a physiological inhibitor of the Raf-mitogen-activated protein kinase kinase (MEK)-extracellular-signal-regulated kinase (ERK) pathway [16].…”

Section: Introductionmentioning

confidence: 99%

Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance

Chen

Lian

et al. 2015

Gastric Cancer

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Background B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP) are involved in cancer metastasis and chemotherapeutic resistance, respectively. In this study, we evaluated the association between Bmi-1 and RKIP and outcome of gastric cancer through clinical data analysis and in vitro experiments. Methods Bmi-1 expression and RKIP expression were observed in 107 cases of gastric cancer through use of tissue microarray technology to identify their correlations with clinicopathological parameters, patient survival, and susceptibility to chemotherapy. The correlation was confirmed in gastric cancer cell lines, analyzed further by gene overexpression and silencing analysis, a cell invasion assay, and a chemosensitivity test.Results Positive expression of Bmi-1 was highly correlated with T classification and clinical stage. Diminished or lost expression of RKIP was significantly associated with T classification, lymph node metastasis, distant metastasis, and clinical stage. Bmi-1 is negatively and RKIP is positively related to patient survival. Positive expression of Bmi-1 and negative expression of RKIP are associated with poor patient survival and modest efficacy of postoperative chemotherapy. A meaningfully inverse association between Bmi-1 and RKIP was found in tissue microarray studies, and was verified further in gastric cancer cell lines. Moreover, gene overexpression and silencing analysis indicated that RKIP might be regulated by Bmi-1. Furthermore, the impacts of Bmi-1 on cell invasion and chemotherapy resistance were rescued by knockdown of RKIP. Conclusions Our study implies that detection of Bmi-1 and RKIP is valuable in predicting patient survival and therapeutic response in gastric cancer, and the inverse association between Bmi-1 and RKIP reveals the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance.Y. Chen, G. Lian, and G. Ou are contributed equally to this work.Electronic supplementary material The online version of this article

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“…The structure of the RKIP/PEBP proteins is characterized by a central ␤-sheet surrounded by more variable ␤-strands and ␣-helices (12)(13)(14). These secondary structural elements are connected by long loops.…”

mentioning

confidence: 99%

“…phosphates, and is implicated in the binding of RKIP to Raf1 (14 -18). Due to this binding pocket and due to the ability of RKIP to interfere with various signaling cascades and cellular functions, RKIP has been suggested as a major modulator of kinases involved in signal transduction (12,19).…”

mentioning

confidence: 99%

Raf Kinase Inhibitor Protein (RKIP) Dimer Formation Controls Its Target Switch from Raf1 to G Protein-coupled Receptor Kinase (GRK) 2

Deiss

Kisker

Lohse

et al. 2012

Journal of Biological Chemistry

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Background: Raf kinase inhibitor protein (RKIP) is a regulator of several distinct kinases, including Raf1 and G proteincoupled receptor kinase 2 (GRK2). Results: Protein kinase C-mediated phosphorylation of RKIP triggers dimer formation of RKIP, which enables RKIP to switch specificity between Raf1 and GRK2. Conclusion: Phosphorylation-dependent dimerization of RKIP coordinates specific interactions with Raf1 and GRK2. Significance: Control switches in a kinase regulator permit specific control of multiple kinase signaling pathways and their downstream functions.

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Raf kinase inhibitory protein: a signal transduction modulator and metastasis suppressor

Cited by 144 publications

References 51 publications

Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients

Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients

Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance

Raf Kinase Inhibitor Protein (RKIP) Dimer Formation Controls Its Target Switch from Raf1 to G Protein-coupled Receptor Kinase (GRK) 2

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