RHAMM/HMMR: An Itinerant and Multifunctional Hyaluronan Binding Protein That Modifies CD44 Signaling and Mitotic Spindle Formation

RHAMM is a gene that belongs to a multifunctional group of cytoplasmic proteins, which are unconventionally exported to the cell surface in response to specific stimuli. This process is highly active during response to injury and tumorigenesis and in certain situations/phenotypic backgrounds, RHAMM, or structural variants of RHAMM, can act as an oncogene. The prognostic value of RHAMM is linked to specific subtypes of organ-specific malignancies, which have distinct anatomic and molecular pathologies that are correlated to different outcomes. RHAMM levels can be used as one marker to further classify specific tumors or to target RHAMM for therapy in such tumor subtypes. Several studies suggest that mutations in RHAMM may affect oncogenic properties. Cell surface RHAMM performs co-receptor functions by affecting signaling through hyaluronan and growth factor receptors while intracellular RHAMM is a mitotic spindle protein that interacts with BRCA1/BARD1 complexes to control mitotic spindle stability. Further analyses of the molecular mechanisms by which RHAMM regulates these processes will undoubtedly identify new "inside-outside" paradigms that control motility and mitosis and may lead to the identification of novel key signaling/structural nodes that can be targeted in the treatment of chronic inflammation or cancer.