Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions?
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.
Maxwell
Christopher Alan
CA
Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain. cmaxwell@ico.scs.es
McCarthy
James
J
Turley
Eva
E
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*
D019313:BRCA1 Protein; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor