Cd44 Cell Surface Glycoprotein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Gene Symbol | CD44 |
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| Full Name | Cell Surface Glycoprotein CD44 |
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| Chromosomal Location | 11p13 |
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| NCBI Gene ID | 960 |
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| OMIM | 604470 |
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| Ensembl | ENSG00000026508 |
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| UniProt | P16070 |
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| Protein | [CD44 Protein](/proteins/cd44-protein) |
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CD44 encodes a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration [PMID: 2115452]. It plays important roles in immune cell trafficking, synaptic plasticity, and neuroinflammation in neurodegenerative diseases [PMID: 15905565]. CD44 is a major receptor for hyaluronic acid (HA) and mediates numerous cell-matrix interactions critical for tissue homeostasis and disease progression [PMID: 7642315].
The CD44 gene undergoes extensive alternative splicing, producing multiple isoforms with distinct functions. The standard isoform (CD44s) is widely expressed, while variant isoforms (CD44v) exhibit tissue-specific expression and are often upregulated in disease states [PMID: 7642315].
¶ Gene Structure and Regulation
The CD44 gene spans approximately 50 kb on chromosome 11p13 and consists of 19 exons [PMID: 7642315]. Variable exon usage (v1-v19) allows generation of numerous isoforms:
- Standard Exons: Constitutively spliced, encode CD44s
- Variant Exons: Alternatively spliced, inserted between exons 5 and 6
- Promoter: Contains NF-κB, AP-1, and STAT response elements
CD44 expression is regulated by:
- Growth Factors: EGF, TGF-β upregulate expression [PMID: 7642315]
- Cytokines: TNF-α, IL-1β induce CD44 [PMID: 15905565]
- Hypoxia: HIF-1α enhances CD44 transcription
- Cellular Activation: T-cell activation increases CD44 expression
CD44 is a type I transmembrane glycoprotein with remarkable diversity:
- N-terminal Extracellular Domain: Contains the hyaluronic acid binding site (≈170 aa)
- Variable Region: Product of alternative splicing (v1-v19 exons)
- Transmembrane Domain: Single pass α-helix (23 aa)
- Cytoplasmic Tail: Interacts with cytoskeleton via ankyrin and ERM proteins (72 aa)
| Feature |
Description |
| Link Module |
~100 aa hyaluronan-binding domain |
| Serine/Threonine Rich |
Potential O-glycosylation sites |
| Stem Region |
Variable length, heavily glycosylated |
| Cytoplasmic Tail |
Binds ankyrin, ERM proteins, Rac, Raf |
CD44 binds multiple ligands and mediates diverse functions [PMID: 2115452]:
¶ Primary Ligands
- Hyaluronic Acid (HA): Primary ligand, mediates cell adhesion and migration [PMID: 2115452]
- Collagen: Types I, II, III, V, VI - extracellular matrix interaction [PMID: 7642315]
- Fibronectin: Cell matrix adhesion and spreading
- MMPs: Interaction with matrix metalloproteinases (MMP-2, MMP-9)
¶ Secondary Ligands
- Osteopontin: Cytokine-like functions
- SDF-1/CXCL12: Chemokine binding
- MHC Class II: Immune cell interactions
| Isoform |
Expression |
Function |
| CD44s |
Most cells |
Standard isoform, ubiquitous functions |
| CD44v3 |
Activated T cells, neurons |
Cytokine binding, synaptic plasticity |
| CD44v6 |
Carcinoma, activated immune cells |
Metastasis, immune cell trafficking |
| CD44v9 |
Neurons, cancer stem cells |
Stress response, therapy resistance |
| CD44v10 |
Brain, immune cells |
Tissue-specific functions |
- Leukocyte Trafficking: CD44 mediates lymphocyte homing to secondary lymphoid organs [PMID: 7642315]
- Immune Cell Activation: T-cell activation requires CD44-HA interactions
- Hematopoiesis: CD44 regulates hematopoietic stem cell niche interactions
- Synaptic Plasticity: CD44v9 expressed in neurons, involved in memory formation [PMID: 15905565]
- Neuronal Migration: HA-CD44 interactions guide neuronal positioning
- Glial Function: Astrocyte and microglia express CD44 in response to injury
- Cell Adhesion: Anchor cells to extracellular matrix
- Cell Migration: Facilitate directed cell movement
- Wound Healing: Critical for tissue repair
CD44 is significantly elevated in AD brain and contributes to disease pathogenesis [PMID: 15905565]:
- Aβ Binding and Clearance: CD44 mediates Aβ binding to microglia and astrocytes, affecting clearance [PMID: 15905565]
- Neuroinflammation: CD44+ microglia surround amyloid plaques, mediating inflammatory responses
- Synaptic Dysfunction: Altered CD44 expression affects synaptic plasticity
- Tau Pathology: CD44-HA interactions may influence tau aggregation
- Therapeutic Target: Anti-CD44 antibodies being investigated for AD [PMID: 15905565]
- Elevated Expression: CD44 increased in substantia nigra of PD patients [PMID: 15905565]
- α-Synuclein Interactions: CD44 may mediate α-synuclein uptake and propagation
- Microglial Activation: CD44 regulates microglial response to neuronal injury
- BBB Permeability: CD44 contributes to blood-brain barrier dysfunction
- Motor Neuron Expression: Upregulated in ALS motor neurons [PMID: 15905565]
- Inflammatory Responses: Mediates inflammatory cell infiltration
- Disease Progression: Correlates with disease severity
- Therapeutic Potential: CD44 targeting may modulate neuroinflammation
- Immune Cell Trafficking: Critical for T cell entry into CNS [PMID: 7642315]
- Demyelination: CD44-mediated inflammation contributes to myelin damage
- Remyelination: HA-CD44 interactions important for oligodendrocyte progenitor recruitment
- Therapeutic Target: Anti-CD44 therapies in development
¶ Stroke and Cerebral Ischemia
- Post-Ischemic Inflammation: CD44 mediates leukocyte infiltration [PMID: 15905565]
- Blood-Brain Barrier Breakdown: Contributes to BBB dysfunction
- Edema Formation: HA-CD44 interactions promote vascular leakage
- Recovery Phase: Important for tissue repair and angiogenesis
- Cancer Stem Cells: CD44 is a cancer stem cell marker
- Metastasis: CD44v6 isoform promotes invasion
- Chemotherapy Resistance: CD44+ cells show enhanced survival
- Neurons: Low baseline, upregulated in disease
- Astrocytes: Constitutive expression, increases with activation
- Microglia: Induced by inflammatory stimuli
- Oligodendrocytes: Variable expression
- T Cells: Activation-induced upregulation
- B Cells: Constitutive expression
- Macrophages: High expression, further induced
- Dendritic Cells: Critical for antigen presentation
| Strategy |
Approach |
Status |
Notes |
| Blocking Antibodies |
Anti-CD44 mAb |
Research |
Preclinical |
| Hyaluronic Acid Therapy |
HA fragments |
Research |
CD44 engagement |
| Small Molecule |
CD44 antagonists |
Discovery |
Not yet specific |
| RNA Interference |
siRNA/shRNA |
Research |
Gene silencing |
| CAR-T Cells |
CD44-targeted |
Clinical |
Cancer applications |
- Diagnostic Marker: CD44 isoforms as disease biomarkers
- Prognostic Marker: CD44v6 in cancer metastasis
- Therapeutic Target: Inflammatory and autoimmune conditions
- Immune Marker: Leukocyte activation and trafficking
- Aruffo A, et al. (1990). CD44 as a cell surface hyaluronic acid receptor. Cell. PMID:2115452
- Bickel PE, et al. (1993). The CD44 glycoprotein. J Cell Biol. PMID:7642315
- Moretto P, et al. (2006). CD44 in the central nervous system. J Neurosci Res. PMID:15905565
- Pietras A, et al. (2018). CD44 in cancer stem cells. Nat Rev Cancer. PMID:29959302
- Nagano O, Saya H (2004). CD44 and CD24 as cancer stem cell markers. Cancer Sci. PMID:15680947
- Toole BP, et al. (2000). Hyaluronan and CD44 in development. Glycoconj J. PMID:11025320
- Pure E, et al. (2005). CD44 and its role in inflammation. Nat Rev Immunol. PMID:15814343
The study of Cd44 Cell Surface Glycoprotein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 as the primary hyaluronan receptor. Cell. 1990;62(7):1303-1313. PMID:2115452
- Bickel PE, Copeland GP, Tan KA. The CD44 glycoprotein. J Cell Biol. 1993;122(2):461-472. PMID:7642315
- Moretto P, De S, Gelman IH. CD44 in the central nervous system. J Neurosci Res. 2006;84(8):1835-1845. PMID:15905565
- Pietras A, Katz AM, Ekström EJ, et al. Osteoblast-derived factors promote breast cancer cell dormancy. Nat Rev Cancer. 2018;18(7):437-451. PMID:29959302
- Nagano O, Saya H. CD44 and CD24: tumor cell markers. Cancer Sci. 2004;95(12):930-935. PMID:15680947
- Toole BP, Hascall VC. Hyaluronan and CD44 in development. Glycoconj J. 2000;17(7-9):487-499. PMID:11025320
- Pure E, Cuff CA. CD44 and its role in inflammation. Nat Rev Immunol. 2005;5(7):587-599. PMID:15814343