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Forum on Immunopathological Diseases and Therapeutics
SJR: 0.309 SNIP: 0.041 CiteScore™: 0.18

ISSN Imprimir: 2151-8017
ISSN On-line: 2151-8025

Archives: Volume 1, 2010 to Volume 7, 2016

Forum on Immunopathological Diseases and Therapeutics

DOI: 10.1615/ForumImmunDisTher.v2.i1.30
pages 13-20

Raf Kinase Inhibitory Protein: A Signal Transduction Modulator and Metastasis Suppressor

Eva M. Eves
Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA
Marsha Rich Rosner
Ben May Department for Cancer Research, University of Chicago, Gordon Center for Integrative Sciences, Chicago, Illinois

RESUMO

Cells have a multitude of controls to maintain their integrity and prevent random switching from one biological state to another. Raf Kinase Inhibitory protein (RKIP or PEBP1), a member of the phosphatidylethanolamine-binding protein family, is representative of a new class of modulators of signaling cascades that functions to maintain the balance of biological systems. RKIP inhibits MAP kinase (Raf-MEK-ERK), G protein–coupled receptor (GPCR), and NF-κB-signaling cascades. RKIP targets different kinases dependent on its phosphorylation state, and integrates cross talk initiated by multiple environmental stimuli. We have shown that RKIP is a unique kinase inhibitor and substrate that uses a flexible pocket to integrate ligand-binding and phosphorylation-dependent interactions to modulate the MAPK signaling pathway. This mechanism is likely conserved among RKIP homologues in eukaryotes. RKIP also functions as a suppressor of metastasis. We have identified two mechanisms leading to altered cellular signaling and potentiation of tumorigenesis and metastasis. First, loss or depletion of RKIP results in chromosomal abnormalities and genomic instability via disregulation of the spindle checkpoint. Second, RKIP inhibits a signaling cascade involving MAPK, Myc, LIN28, let-7, and downstream let-7 targets that promotes invasion and metastasis of breast cancer cells. Our results highlight the importance of RKIP as a key metastasis suppressor and potential therapeutic agent.