title: Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions?
abstract: Tumor cells use a wide variety of post-translational mechanisms to modify the functional repertoire of their transcriptome. One emerging but still understudied mechanism involves the export of cytoplasmic proteins that then partner with cell-surface receptors and modify both the surface-display kinetics and signaling properties of these receptors. Recent investigations demonstrate moonlighting roles for the proteins epimorphin, FGF1, FGF2, PLK1 and Ku80, to name a few, during oncogenesis and inflammation. Here, we review the molecular mechanisms of unconventional cytoplasmic-protein export by focusing on the mitotic-spindle/hyaluronan-binding protein RHAMM, which is hyper-expressed in many human tumors. Intracellular RHAMM associates with BRCA1 and BARD1; this association attenuates the mitotic-spindle-promoting activity of RHAMM that might contribute to tumor progression by promoting genomic instability. Extracellular RHAMM-CD44 partnering sustains CD44 surface display and enhances CD44-mediated signaling through ERK1 and ERK2 (ERK1/2); it might also contribute to tumor progression by enhancing and/or activating the latent tumor-promoting properties of CD44. The unconventional export of proteins such as RHAMM is a novel process that modifies the roles of tumor suppressors and promoters, such as BRCA1 and CD44, and might provide new targets for therapeutic intervention.
authors: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain. cmaxwell@ico.scs.es
authors: Christopher Alan
authors: CA
authors: Maxwell
authors: James
authors: J
authors: McCarthy
authors: Eva
authors: E
authors: Turley
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor