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FLASH GENE
Symbol CD44 contributors: shn/pgu - updated : 22-04-2016
HGNC name CD44 molecule (Indian blood group)
HGNC id 1681
Location 11p13      Physical location : 35.160.416 - 35.253.946
Synonym name
  • Lutheran inhibitor, dominant
  • Hermes antigen
  • GP90 lymphocyte homing/adhesion receptor
  • antigen gp90 homing receptor
  • cell surface glycoprotein CD44
  • chondroitin sulfate proteoglycan 8
  • extracellular matrix receptor-III
  • CD44 antigen (homing function and Indian blood group system)
  • cell differentiation antigen CD44 (Pgp-1), identified by antibodies GRHL1, F10-44-2 (including MDU2, MDU3, MIC4 identified by monoclonal antibodies A1G3,13D8,F10.44)
  • phagocytic glycoprotein I
  • hematopoietic cell E- and L-selectin ligand
    • Synonym symbol(s) MDU2, MDU3, MIC4, HCAM, LNHR, CDW44, CSPG8, ECMR-III, HCELL, IN, LHR, MC56, Pgp1, CD44R, HUTCH-I, MGC10468, MIC4
    DNA
    TYPE functioning gene
    STRUCTURE 93.53 kb     18 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map pter - D11S907 - D11S4200 - CD44 - D11S4203 - D11S935 - cen
    RNA
    TRANSCRIPTS type messenger
    text CD44 pre-mRNA produces various mRNA isoforms through alternative splicing of 20 exons, among which exons 1-5 (C1-C5) and 16-20 (C6-C10) are constant exons, whereas exons 6-15 (V1-V10) are variant exons (PMID: 25623890)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    3 splicing 3985 - 139 - -
    also called variant 5
    18 splicing 5748 - 742 - -
    also called variant 1
    9 splicing 4605 - 361 - -
    also called variant 4
    13 splicing 5001 - 493 - -
    also called variant 3
    17 splicing 5619 - 699 - -
    also called variant 2
    - - - - - - 2015 25623890
  • important roles in breast tumor progression and Hodgkin lymphoma
  • HNRNPL is a new regulator for CD44 V10 exon splicing
    • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticthymus   highly
    Digestiveliver   highly
    Endocrinepancreas   highly
    Visualeyeretina    Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Epithelialsecretoryglandularendocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
    VisualMuller cell Homo sapiens
    cell lineage constitutively expressed in parenchymal and hemopoietic cells
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • two clusters of positively charged AAs in a membrane proximal region within the cytoplasmic domain
  • one link domain
  • a TNPO1-specific Nuclear Localization Signal
  • a cytoplasmic domain having no intrinsic kinase activity but has been shown to interact with members of the SRC and RAS family of GTPases
  • ERM binding domain (AAs 292–300) located between the transmembrane domain and the intracellular membrane-proximal domain
    • conjugated GlycoP
    HOMOLOGY
    interspecies ortholog to Cd44, Mus musculus
    ortholog to LOC100330801, Danio rerio
    ortholog to Cd44, Rattus norvegicus
    ortholog to CD44, Pan troglodytes
    Homologene
    FAMILY CD antigens
    CATEGORY adhesion , antigen , receptor
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,nucleus
    text
  • resides in lipid rafts in the cell membrane
  • localizes to the nucleus of several cell types (role of endocytic trafficking in nuclear transport of CD44)
    • basic FUNCTION
  • participates in lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis
  • lymphocyte homing receptor,involved in extracellular matrix adhesion, in myeloid differentiation, lymphocyte activation and lymph node homing
  • main cell surface receptor for hyaluronate adhesion to mucosal high endothelial venule and to type1 and 6 collagen
  • plays a role in resolving lung inflammation
  • mediates macrophage recruitment and protective immunity against tuberculosis
  • plays a role in anchorage of the actin cytoskeleton to the plasma membrane, which is important for cell motility
  • a critical inhibitor of TNF-driven joint destruction and inflammatory bone loss
  • primary cell surface receptor for hyaluronan, binding ligand via a lectin-like fold
  • integral hyaluronan receptor that can promote or inhibit motogenic signaling in tumor cells
  • GLG1, SELPLG and CD44 encompassed all endothelial-selectin ligand activity on neutrophils by using gene- and RNA-targeted loss of function
  • distinct and dynamic contributions of these three glycoproteins in selectin-mediated neutrophil adhesion and signaling
  • may mediate binding of calcium oxalate crystals to tubular epithelia via the ligands osteopontin (OPN) and hyaluronan
  • playing a role in early human nephron formation and branching morphogenesis
  • a significant role in the development of choroidal neovascularization
  • role for CD44 in the pathogenesis of systemic lupus erythematosus and other inflammatory diseases
  • transmembrane glycoprotein that serves as the principal cell surface receptor for hyaluronan (HA) and can affect numerous cellular processes, including cell adhesion, proliferation, and migration
  • imported from the cytoplasm to the nucleus by transportin 1 (TNPO1)where it induces gene transcription
  • early cell surface marker of the Müller glia lineage, and Notch signalling was involved in commitment of retinal progenitor cells to CD44 positive Müller glial precursor cells
  • expanded role for CD44 receptor/ligand interactions in directing cell trafficking via a step 2–bypass pathway of integrin activation
  • presence of Hyaluronan is required for CD44/EGFR coupling following TGFB1 stimulation, in oral fibroblasts
  • critical role for the cell surface molecule CD44 in mediating cell proliferation downstream of oncogenic KRAS signaling
  • unrecognized role for CD44 in oncogenic KRAS-induced lung adenocarcinoma
  • undergoing sequential proteolytic cleavage at the cell surface (pMID: 23884413)
  • is a complex cell adhesion molecule that mediates communication and adhesion between adjacent cells as well as between cells and the extracellular matrix
  • important role for IMPG1 and CD44 in the development of photoreceptors and IPM formation
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS inflammation , cellular trafficking transport
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • chondroitin sulfate, Ii-CS
  • associated with CD4
  • collagen type XIV alpha 1, COL14A1
  • interacts with the ezrin-radixin-moesin family of cytoskeletal adaptors
  • T-lymphocyte specific protein tyrosine kinase p56lck
  • membrane-binding partner for ezrin/radixin/moesin (ERM) proteins
  • versican, VCAN
  • metalloproteinase-9, MMP-9
  • T-cell lymphoma invasion and metastasis 1, TIAM1
  • vav 2 guanine nucleotide exchange factor, VAV2
  • contributes to the endocytosis and metabolism of hyaluroran
  • dentin matrix protein 1, DMP1 and osteopontin, SPP1
  • transforming growth factor, beta receptor 1, TGFBR1
  • ezrin, EZR
  • Protein 4.1 tumor suppressor, Protein 4.1R
  • c-Src kinase
  • Rac1-dependent protein kinase N-gamma, PKNgamma
  • SMAD family member 1, SMAD1
  • epidermal growth factor receptor, EGFR and v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian), ERBB2
  • matrix metallopeptidase 7 (matrilysin, uterine), MPP7
  • RhoA-specific guanine nucleotide exchange factor, p115RhoGEF in human metastatic breast tumor cells (MDA-MB-231 cell line)
  • ankyrin and inositol 1,4,5-triphosphate receptor, type 3, ITPR3
  • glycosaminoglycan hyaluronan receptor
  • HMMR (HMMR and CD44 act together in a hyaluronan-dependent autocrine mechanism to coordinate sustained signaling through ERK1,2, leading to high basal motility of invasive breast cancer cells)
  • cytoskeletal linker protein ezrin (modulated by phosphorylation of Ser291 and this phosphorylation is critical for CD44-dependent directional cell motility)
  • receptor-ligand relationships between CD44 and LGALS8, interactions which may affect the extent of the autoimmune inflammatory response in the synovial fluid of rheumatoid arthritis patients
  • hyaluronan (hyaluronan induces cell death in activated T cells through CD44)
  • physical association between CD44 and ITGA4
  • CD44 is the first identified endogenous ligand of CLEC4G, and similarly, that CLEC4G is a novel ligand of CD44
  • interacting with SELL (TM domains of SELL and CD44 play a crucial role in cell adhesion under flow by targeting receptors to microvilli or the cell body, respectively)
  • interacts with importin family members and this transportin-dependent pathway is the mechanism whereby full-length CD44 enters the nucleus
  • functional interaction with transportin requires the membrane-proximal 20 AAs of the cytoplasmic tail of CD44 that contain the TNPO1-specific NLS
  • interacting with MMP9 (initiates cross-talk between CD44 and EGFR, which in turn activates downstream effectors for cell migration)
  • major hyaluronan (HA) receptor, taht is a novel partner for podoplanin (PDPN)
  • role of MARCH8 and MARCH4 in the regulated turnover of CD81 and CD44, two ubiquitously expressed, multifunctional proteins
  • in the presence of an hyaluronan-rich matrix, HA (hyaluronan) binds to CD44 and alters a fibroblast proliferative response to TGFB1, whereas in a non-HA-rich environment, TGFB1 mediates its responses through other CD44-independent pathways, such as the Smad pathway
  • MARCH8 expression completely shifted the trafficking of CD44 and CD98 proteins away from recycling tubules to early endosome antigen 1 compartments and late endosomes, resulting in reduced surface levels
  • LRP1-mediated internalization of CD44 appeared critical to define the adhesive properties of tumor cells
  • MME might be involved in the development of endometriosis due to its influence on CD44-dependent cell adhesion
  • CD44 of control chondrocytes was found to interact and co-immunoprecipitate with both the 65- and 130-kDa isoforms of ANK3
  • SND1 promotes the inclusion of CD44 variable exons by recruiting KHDRBS1 and spliceosomal components on CD44 pre-mRNA
  • CD44 is a key downstream target of HNRNPM
  • PRG4 (lubricin) is a novel putative ligand for CD44 and may control synoviocyte overgrowth in inflammatory arthropathies via a CD44-mediated mechanism
  • interaction of TM4SF5 with CD44 promotes self-renewal and circulating capacities of hepatocarcinoma cells
  • PRG4 may play a role in modulating inflammatory responses through interaction with CD44
  • important role for IMPG1 and CD44 in the development of photoreceptors and IPM (interphotoreceptor matrix) formation during human retinogenesis
    • cell & other
    REGULATION
    inhibited by p53 via binding to a noncanonical p53-binding sequence in the CD44 promoter
    Other processed by membrane-type-1 matrix metalloproteinase,MT1-MMP
    phosphorylated by protein kinase C
    is cleaved, releasing a C-terminal intracellular domain with unknown function in the cytoplasm
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral       gain of function
    in gastric cancer (may be associated with alternative splicing)
    tumoral       loss of function
    by aberrant methylation of promoter of exon 1 in neuroblastoma
    tumoral       gain of function
    in breast cancer
    tumoral       loss of function
    in breast cancer, amplified in gastric cancer (maybe associated with alternative splicing)
    tumoral       loss of function
    in prostate carcinoma (primary or with metastases)
    tumoral     --over  
    of CD44v6, especially in early-onset gastric carcinomas
    tumoral     --over  
    may be an independent unfavorable prognostic factor for overall survival in advanced CRC, especially stage IV disease
    constitutional     --over  
    higher levels of CD34, CD44, and LIF were found in the placentas of pre-eclamptic compared with normotensive women
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurosensorial  
    inhibition of HA-CD44 interaction leads to significant suppression of inflammation-related choroidal neovascularization (CNV) indicating the possibility of HA-CD44 blockage as a therapeutic target for inhibiting CNV in age macular dystrophy
    cancerlung 
    targeting CD44 could be an effective strategy for halting Kras-dependent carcinomas
    ANIMAL & CELL MODELS
  • any obvious developmental or neurological deficits in mice in which expression of all known isoforms of CD44 is abolished
  • CD44-deficient fibroblasts were highly tumorigenic in nude mice
  • In CD44(-/-) mice, postpartum uterine involution is accelerated and maintenance of lactation is impaired
  • CD44-deficient mice succumb to unremitting inflammation following noninfectious lung injury
  • Macrophage recruitment into M. tuberculosis-infected lungs and delayed-type hypersensitivity sites is impaired in CD44-deficient CD44-/- mice. CD44-/- mice displayed a decreased survival and an enhanced mycobacterial outgrowth in lungs and liver during pulmonary tuberculosis
  • CD44(-/-) human TNF-transgenic mice display severe generalized osteopenia and an increased bone resorption due to enhanced number, size, and resorptive capacity of osteoclasts