{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRHAMM (also known as HMMR or CD168) functions as an alternative hyaluronan receptor that, when CD44 is absent or insufficient, mediates increased binding of hyaluronic acid to promote cell motility, inflammation, and tumor progression. For example, in collagen‐induced arthritis, the loss of CD44 leads to greater HA accumulation and augmented RHAMM signaling that exacerbates joint inflammation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]. In aggressive fibromatosis, RHAMM is highly expressed and its absence significantly reduces tumor formation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "]. A similar compensatory mechanism is observed during Cryptococcus neoformans brain invasion, where RHAMM expression in CD44‐deficient mice contributes to host cell interactions ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "]. Furthermore, in islet cell tumor models, the RHAMM isoform B promotes metastatic growth through EGFR and downstream signaling ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "], while in acute lung injury, macrophage‐targeted overexpression of RHAMM leads to worsened inflammation and fibrosis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "]. In androgen‐dependent prostate cancer, deregulated HA–RHAMM signaling appears to foster tumorigenicity and metastasis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "], and expression of altered RHAMM proteins accelerates pancreatic cancer progression in the setting of compromised p53 function ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "]. In addition, hijacking of the unfolded protein response by RHAMM during persistent ER stress contributes to HBV‐induced hepatocellular carcinoma ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "], and its ability to sustain CD47 “don’t eat me” signaling aids tumor immune escape in liver cancer ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nApart from its extracellular receptor role, RHAMM plays a prominent intracellular part in regulating cytoskeletal dynamics and cell cycle progression. Specific isoforms associate with microtubules, mitotic spindles, and centrosomes where they control spindle integrity and microtubule polymerization via ERK1/2–MEK1 complexes ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "]. RHAMM also localizes at centrosomes to influence the positioning of cortical NuMA–dynein complexes in a PLK1‐dependent manner, thereby ensuring correct spindle orientation during progenitor cell divisions ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "]. In osteoblastic and other differentiation contexts, overexpression of RHAMM activates ERK1/2 to promote proliferation while suppressing differentiation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "]. In embryonic stem cells, RHAMM is required for maintaining pluripotency through modulation of signal transduction cascades associated with the microtubule network ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "]. Moreover, deletion of critical RHAMM domains disrupts spindle orientation in granulosa cells, leading to defects in folliculogenesis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "], while in neuronal cells, RHAMM enhances microtubule stability and promotes neurite formation through its interaction with non‐centrosomal microtubule nucleators ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRHAMM also exerts significant influence on tissue development, repair, and regeneration. During embryonic myogenesis, hyaluronan interactions with RHAMM promote the migration and proliferation of myogenic progenitors, thus contributing to proper muscle formation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "]. In the adult brain’s neurogenic regions, sustained hyaluronan levels along with RHAMM expression in migrating neuroblasts suggest a role in facilitating neural cell migration ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "]. In the context of cutaneous repair, RHAMM coordinates the opposing motogenic activities of fibroblasts and keratinocytes—suppressing keratinocyte motility while enhancing fibroblast migration—to ensure proper wound closure ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "]. Lastly, the discovery of a Cd168⁺ skeletal stem/progenitor cell population with high replicative and osteochondrogenic potential highlights a regenerative role for RHAMM in long bone development and repair ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "].\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shlomo Nedvetzki, Erez Gonen, Nathalie Assayag, et al. 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