RHAMM Is a Centrosomal Protein That Interacts with Dynein and Maintains Spindle Pole Stability

Abstract

The receptor for hyaluronan-mediated motility (RHAMM), an acidic coiled coil protein, has previously been characterized as a cell surface receptor for hyaluronan, and a microtubule-associated intracellular hyaluronan binding protein. In this study, we demonstrate that a subset of cellular RHAMM localizes to the centrosome and functions in the maintenance of spindle integrity. We confirm a previous study showing that the amino terminus of RHAMM interacts with microtubules and further demonstrate that a separate carboxy-terminal domain is required for centrosomal targeting. This motif overlaps the defined hyaluronan binding domain and bears 72% identity to the dynein interaction domain of Xklp2. RHAMM antibodies coimmunprecipitate dynein IC from Xenopus and HeLa extracts. Deregulation of RHAMM expression inhibits mitotic progression and affects spindle architecture. Structure, localization, and function, along with phylogenetic analysis, suggests that RHAMM may be a new member of the TACC family. Thus, we demonstrate a novel centrosomal localization and mitotic spindle-stabilizing function for RHAMM. Moreover, we provide a potential mechanism for this function in that RHAMM may cross-link centrosomal microtubules, through a direct interaction with microtubules and an association with dynein.

RHAMM expression and isoform balance predict aggressive disease and poor survival in multiple myeloma

“…Within both mitotic and unsynchronized populations of cycling cell lines, the level of RHAMM FL was much greater than RHAMM Ϫexon4 . This fits with our previous work suggesting that RHAMM may function in the cross-linking and stabilization of the mitotic spindle, through microtubule contacts at its NH 2 -and COOH-termini 15 ; as RHAMM Ϫexon4 is inhibited in its NH 2 -terminal interphase microtubule interactions and may not associate/ stabilize spindle poles as efficiently as RHAMM FL , amplified expression of this variant during mitosis may have debilitating effects on spindle integrity. Thus, while increases in RHAMM expression levels could reflect in part the mitotic rate in MM PCs, increases in RHAMM exon 4 splicing are not expected to be associated with an increased mitotic rate.…”

“…13 RHAMM FL has been described as an actin-and microtubule-associated protein that localizes to the centrosome and mitotic spindle pole and is essential for mitotic stability. 14,15 The NH 2 -terminus of RHAMM directly interacts with microtubules, via exon 4, while the COOH-terminus targets the centrosome, presumably through an indirect interaction with dynein. 14,15 Loss of exon 4 inhibits the ability of RHAMM to interact with interphase microtubules 14 ; disruption of the COOHterminus, by microinjection of polyclonal antiserum, affects mitotic integrity and induces tripolar and tetrapolar spindles.…”

“…14,15 The NH 2 -terminus of RHAMM directly interacts with microtubules, via exon 4, while the COOH-terminus targets the centrosome, presumably through an indirect interaction with dynein. 14,15 Loss of exon 4 inhibits the ability of RHAMM to interact with interphase microtubules 14 ; disruption of the COOHterminus, by microinjection of polyclonal antiserum, affects mitotic integrity and induces tripolar and tetrapolar spindles. 15 While RHAMM is ubiquitously expressed in murine tissues (with elevated expression in testis, thymus, and spleen), 16 consistent detection of RHAMM expression within healthy human tissues appears to be limited to the testis.…”

“…14,15 Loss of exon 4 inhibits the ability of RHAMM to interact with interphase microtubules 14 ; disruption of the COOHterminus, by microinjection of polyclonal antiserum, affects mitotic integrity and induces tripolar and tetrapolar spindles. 15 While RHAMM is ubiquitously expressed in murine tissues (with elevated expression in testis, thymus, and spleen), 16 consistent detection of RHAMM expression within healthy human tissues appears to be limited to the testis. 17,18 Reports of RHAMM expression have identified the testis, spleen, colon, and stomach 17 ; the testis, placenta, and thymus 18 ; and the testis, placenta, lung, and pancreas 19 as RHAMMpositive tissues (in decreasing orders).…”

Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer

“…1 RHAMM binds hyaluronan, 2 interacts with both mictotubules and microfilaments, 3,4 localizes to the centrosome maintaining the spindle integrity 5 and is suggested to represent a member of the MAP family. 3 RHAMM is involved in cell motility and signaling 6 as well as oncogenic events.…”