HMMR - hyaluronan mediated motility receptor |Elisa - Clia - Antibody - Protein

Background

The hyaluronan-mediated motility receptor (HMMR), also known as RHAMM (Receptor for Hyaluronan-Mediated Motility), is a protein encoded by the HMMR gene in humans. Originally identified in studies focusing on cancer cell motility, HMMR functions as a receptor for hyaluronan (HA), a component of the extracellular matrix (ECM) involved in tissue hydration, structural integrity, and cellular communication. HMMR has attracted significant scientific interest due to its roles in cellular adhesion, proliferation, migration, and wound healing. Its expression is often upregulated in cancer cells, contributing to increased cell motility and invasiveness, making it a focal point in oncology research.

HMMR functions not only as a surface receptor but also intracellularly, interacting with various signaling pathways and microtubule networks, which influences cell division and chromosomal stability. Given its involvement in pathways like RAS and ERK and its interaction with the mitotic spindle, HMMR is critical in cell cycle regulation and tissue morphogenesis. Dysregulated HMMR expression has been associated with cancer progression, inflammatory diseases, and even osteoarthritis, placing it at the intersection of various physiological and pathological processes.

Protein Structure

HMMR has a unique and versatile structure that enables both extracellular and intracellular functions. The structural features of HMMR include:

N-terminal Hyaluronan Binding Domain:

• The N-terminal domain is the primary region responsible for HA binding. This domain contains positively charged amino acids that interact electrostatically with the negatively charged HA.
• The binding of HA to this domain induces conformational changes that promote receptor dimerization, activating downstream signaling cascades that influence cellular adhesion, motility, and invasion. This binding domain is crucial for HMMR's role as an ECM receptor, facilitating cell-ECM interactions.

Central Coiled-coil Region:

• The central region of HMMR consists of a coiled-coil structure that mediates interactions with other proteins, such as ERK (extracellular signal-regulated kinase) and tubulin. This region facilitates HMMR’s association with intracellular signaling proteins and cytoskeletal elements, impacting cell migration and mitotic spindle organization.
• The coiled-coil structure also stabilizes HMMR in its active form, enabling it to function in the cell cycle and mitosis by maintaining its structural integrity during interactions with other proteins.

C-terminal Domain:

• The C-terminal region of HMMR contains binding sites for intracellular signaling proteins and microtubules, particularly in the mitotic spindle apparatus. This domain’s interactions with proteins such as the mitotic kinesin-like protein help regulate mitosis and chromosome stability.
• The C-terminal domain is also involved in the regulation of the mitotic spindle checkpoint, ensuring proper chromosome segregation during cell division. This function is particularly relevant in cancer, where HMMR overexpression can lead to chromosomal instability.

Intracellular Localization Signals:

• HMMR possesses nuclear localization signals and sequences allowing it to shuttle between the cell membrane and intracellular compartments. This dynamic localization allows HMMR to function in both extracellular signal reception and intracellular signaling, integrating external and internal stimuli.

Classification and Subtypes

HMMR belongs to the hyaluronan receptor family, a group of proteins that interact with HA and participate in various cellular processes. Unlike other HA receptors such as CD44, HMMR is multifunctional, with distinct membrane-bound and intracellular activities. HMMR exists primarily as a single isoform, though post-translational modifications can alter its localization and function. Variations in HMMR expression are influenced by tissue type, cell cycle phase, and cellular context, with cancer cells often exhibiting high levels.

Function and Biological Significance

The main functions and biological roles of HMMR involve:

Cell Adhesion and Migration:

• HMMR’s binding to HA promotes cellular adhesion to the ECM, contributing to cell motility and invasion. This function is essential in wound healing and tissue regeneration, where HMMR expression is upregulated to facilitate cell movement to injury sites. Through HA interactions, HMMR activates pathways that remodel the actin cytoskeleton, facilitating cell migration.

Signal Transduction:

• HMMR activates multiple signaling pathways upon HA binding, including RAS, ERK1/2, and phosphoinositide 3-kinase (PI3K). These pathways regulate cellular proliferation, differentiation, and survival. HMMR’s interaction with ERK enables it to influence gene expression related to cell growth and apoptosis, linking it to cancer progression.
• The activation of PI3K by HMMR plays a critical role in cell survival, promoting anti-apoptotic signaling that is beneficial for tumor growth and maintenance.

Mitotic Spindle Formation and Chromosomal Stability:

• Intracellularly, HMMR associates with microtubules and the mitotic spindle, playing a role in mitosis. This interaction is critical for proper chromosome alignment and segregation, ensuring genomic stability during cell division.
• HMMR overexpression disrupts normal mitotic processes, leading to chromosomal instability—a hallmark of cancer. By influencing the mitotic spindle checkpoint, HMMR can contribute to aneuploidy and tumorigenesis.

Role in Immune Response and Inflammation:

• HMMR is expressed in various immune cells, where it participates in immune responses and inflammation. In macrophages, HMMR interaction with HA triggers the production of pro-inflammatory cytokines, contributing to inflammation. This role is relevant in chronic inflammatory diseases and fibrosis, where excessive HMMR activity exacerbates inflammatory responses.

Clinical Issues

HMMR dysregulation has significant clinical implications, particularly in cancer and inflammatory diseases.

Cancer:

• HMMR is frequently overexpressed in various cancers, including breast, lung, colon, and ovarian cancers. This overexpression is associated with increased tumor cell proliferation, migration, and invasiveness. High HMMR levels are often correlated with poor prognosis, as they contribute to cancer metastasis and chemoresistance.
• Targeting HMMR in cancer therapy is being explored, with a focus on inhibiting its HA binding and disrupting downstream signaling pathways. Reducing HMMR levels has shown promise in preclinical studies, leading to decreased tumor growth and invasiveness.

Fibrosis and Chronic Inflammatory Diseases:

• HMMR plays a role in chronic inflammatory diseases such as rheumatoid arthritis and fibrosis. In these conditions, HMMR activity exacerbates inflammatory responses by promoting immune cell adhesion and migration. Its involvement in macrophage-mediated inflammation suggests that HMMR may be a therapeutic target for reducing chronic inflammation and tissue fibrosis.

Osteoarthritis:

• Increased HMMR expression in osteoarthritic cartilage suggests its involvement in cartilage degeneration. Through HA binding, HMMR modulates the activity of chondrocytes, the cells responsible for cartilage maintenance. Inhibiting HMMR could potentially reduce cartilage breakdown, offering a therapeutic approach for osteoarthritis.

Target in Therapy:

• Due to its dual role in cancer progression and inflammation, HMMR is considered a potential therapeutic target. Anti-HMMR therapies, including HA analogs and monoclonal antibodies, are being developed to inhibit HMMR-HA interactions and downstream signaling.

Summary

HMMR is a multifunctional receptor that plays a pivotal role in cellular motility, proliferation, and signaling by interacting with HA in the ECM and participating in mitotic spindle assembly. Its structure, including the HA-binding domain, coiled-coil region, and C-terminal signaling sites, supports a range of functions from ECM adhesion to mitotic regulation. HMMR’s roles in cell migration, chromosomal stability, and immune response make it critical in tissue repair and remodeling, with dysregulation implicated in cancer metastasis, inflammatory diseases, and osteoarthritis. High HMMR expression in tumors contributes to increased invasiveness and poorer patient prognosis, while its involvement in chronic inflammation and immune cell migration links it to various inflammatory conditions.

The study of HMMR’s structure and signaling functions has expanded our understanding of ECM interactions and cellular motility, establishing HMMR as a potential therapeutic target. Inhibiting HMMR-HA interactions may provide a novel approach to cancer and inflammatory disease treatments, as it could limit tumor invasiveness and reduce inflammatory damage. As research progresses, HMMR continues to reveal its importance in maintaining cellular structure, function, and integrity within complex tissue environments.