Receptor for hyaluronan-mediated motility (RHAMM), a hyaladherin that regulates cell responses to growth factors

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

“…6, which is published as supporting information on the PNAS web site). A survey of the literature for HABPs suggested RHAMM as a possible candidate for a CD44-compensating molecule, because this hyaladherin binds to HA (but not to CS) (38)(39)(40), mediates leukocyte trafficking (17), and promotes expression of both jun and fos in response to HA (19). Therefore, if CIA in CD44-knockout mice is RHAMM-dependent, this phenomenon should be associated with HA rather than with CS interaction.…”

“…Cell surface CD44 may primarily influence the joint inflammatory cascade in WT mice by its ability to quantitatively compete with cell surface RHAMM for HA and͞or its ability to regulate the potency of RHAMM-mediated signaling that may or may not be HAdependent. In the absence of CD44, i.e., in CD44-deficient mice, the highly potent cell surface RHAMM can induce an even more aggressive response that at least in part is caused by its interaction with HA (19). In line with this view, greater HA accumulation was detected in the arthritic joints of CD44-deficient mice than in those of WT mice, because in the latter cell surface CD44 (but not RHAMM) could promote endocytosis of HA and its subsequent delivery for lysosomal digestion (9).…”

“…Although RHAMM is not hyperexpressed in the absence of CD44, other proinflammatory genes, many of which have been linked to RHAMM and are regulated through RHAMM signaling, are activated in arthritic CD44 Ϫ/Ϫ mice. For example, RHAMM is required for activation of signaling pathways through IL-1␤ and TNF-␣, such as erk, and AP-1 (14,19). RHAMM also binds to calmodulin (16), regulates connexin expression (43), and promotes formation of diacylgycerol in response to hyaluronan, linking this hyaladherin to phospholipase C␥ (44).…”

“…Like CD44, RHAMM is subject to alternative splicing (14)(15)(16)(17), particularly during tissue repair or after neoplastic conversion (17). After its interaction with HA, this receptor delivers signals for cell migration and proliferation in normal and malignant cells (15,(17)(18)(19).…”

Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor)

“…Rhamm occurs on the cell surface, as a peripheral or GPI-linked protein, and such intracellular compartments as the cell nucleus, cytoskeleton, podosomes, lamellae and mitochondria (Turley et al, 1990;Pilarski et al, 1994;Zhang et al, 1998;Assmann et al, 1999;Lynn et al, 2001). Rhamm expression is low or undetectable in most normal tissues, but is upregulated following wounding in vivo , culture at low confluence in vitro in the presence of growth factors (Turley and Auersperg, 1989;Hardwick et al, 1992;Cheung et al, 1999;Savani et al, 2001) or upon neoplastic transformation in vitro (Hall et al, 1995) and in vivo (Tammi et al, 2002;Turley et al, 2002). For instance, high expression of human Rhamm is prognostic of a poor outcome in some tumors (Wang et al, 1998;Li et al, 2000;Assmann et al, 2001) and high Rhamm expression is characteristic of many aggressive human neoplasms (Crainie et al, 1999).…”