CD168 HMMR (hyaluronan-mediated motility, RHAMM (receptor for hyaluronan-mediated motility)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Unknown
Sperm
Breast
Dendritic Cell
Myeloid Cell
Myelomonocytic cell
Cancer cell
B Cell
Endothelium
Muscle, Smooth
Fibroblast
Neuronal Cell
Epithelium
T Cell
Monocyte
Peripheral blood
80 / 80
84 / 84
88 / 88

Expression
CD168 is expressed on myelomoncytic lineage and dendritic cells.  It is absent from the majority of lymphocytes but is expressed on granulocyte-colony stimulating factor (G-CSF), mobilized myeloid progenitors.  CD168 is expressed on the cell surface but the protein has no signal sequence or transmembrane domain.  CD168 is expressed as an intracellular protein in breast cancer cell lines and in normal breast tissue.  Expression is strongly expressed by B cell malignancies, acute myeloid leukemias, in neuronal cells, fibroblasts, sperm, respiratory epithelium, endothelium and smooth muscle cells.  Expression is at low to moderate levels in most CD3+ and CD4+/CD8+ thymocytes and some single positive thymocytes.  Resting peripheral blood B cells do not express CD168 whereas 10-30% of peripheral blood T cells are CD168+.  Activation leads to transient upregulation of expression in both T cell and B cells.  Most peripheral blood monocytes have a moderate to strong expression of CD168.  CD34+CD45 lo hematopoietic progenitors have weak surface expression of CD168 but at high intracellular levels.  Most hematopoietic cell lines express CD168, however, expression levels vary when the cells are passaged.

Structure
MOLECULAR FAMILY NAME:  Belongs to the hyaladherin protein family.

CD168 is an acidic coiled protein.  It lacks a signal sequence and transmembrane domain but acts as a cell-surface and intracellular hyaluronan binding protein.  It contains a coiled structure which has a globular domain which interacts with hyaluronan through 2 carboxy-terminal motifs which bind for interphase and mitotic microtubules.  The extensive coiled coil structure has a basic amino terminal globular domain and interacts with hyaluronan through the carboxy-terminal basic 9-11 aa motifs.  The coiled structure which has a globular domain and interacts with hyaluronan through these motifs which bind for interphase and mitotic microtubules.  CD168 contains a 47 aa short cytoplasmic tail which contains a PKC motif but has no potential tyrosine-based motifs.  CD168 participates in hyaluronan dependent motile behavior of thymocytes, lymphocytes, hematopoietic progenitor cells and malignant B lymphocytes.  Both surface and intracellular forms of CD168 can be detected in various cell types.  Intracellular CD168 predominates in adherent cells.  No correlation between the level of hyaluronan mRNA and protein expression with known metastatic/malignant potential of the tumor cell lines was observed.  

MOLECULAR MASS
Cell Type Unreduced Reduced
Recombinant CD168 isoforms in COS cells 88 kDa, 84 kDa, 80 kDa
Thymocytes 88 kDa, 84 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 3 different isoforms.  These isoforms occur in leukocytes and are the full length form of 725 aa.  In multiple myeloma B and plasma cells, 2 splice isoforms are detected with 1 lacking exon 4 and 1 lacking exon 13.  Cervical cancer cell lines express a 3rd splice variant lacking both exon 4 and 13.  TGF-b1 induces multiple protein interactions with 3'UTR of CD168 mRNA which increases trnscript half-life 3 fold.

POST-TRANSLATIONAL MODIFICATION: No information.


Ligands
CD168 associates with CD44.

LIGANDS AND MOLECULES ASSOCIATED WITH CD168
Molecule Comment
Ras CD168 appears to co-localize with ras
Src CD168 co-localizes and co-immunoprecipitates with src
Erk Dominant negative CD168 co-immunoprecipitates with erk and MAPKK
MAPKK Dominant negative CD168 co-immunoprecipitates with erk and MAPKK
Actin CD168 co-sediments with actin and binds calmodulin in a Ca2++ dependent manner
Calmodulin CD168 co-sediments with actin and binds calmodulin in a Ca2++ dependent manner


Function
CD168 is an oncogene with both extracellular and intracellular function.   CD168 is required for ras-transformation of fibroblast cell lines, tumor progression and metastasis, suggesting it may play a role in human oncogenesis.  It mediates hyaluronan-specific motility in a variety of cell types, regulates progression through the G2M of the cell cycle and is required for both hyaluronan and PDGF mediated activation of erk kinase.  It has been shown to interact with the mitotic spindle assembly factors dynein and TPX2.  Expression of CD168 and TPX2 is increased during mitosis, and together they maintain spindle integrity after spindle assembly.  However, if CD168 is over-expressed, spindle architecture is affected.  This finding has led to the hypothesis that over-expression in human tumors affects the centrosomal structure and spindle integrity and potentially modulates apoptotic and cell cycle progression pathways.  
CD168 is involved in the adhesion of early thymocyte progenitors to matrix and its interactions with HA can mediate signals to other cell adhesion molecules.  On the cell surface, CD168 is a significant HA-binding receptor and antibodies to CD168 inhibit both HA-binding and HA-dependent motility of white blood cells.  CD168 is overexpressed at the level of transcripts and on the cell surface of malignant B lymphocytes.  The receptor for hyaluronan mediated motility has been reported to mediate migration, transformation and metastic spread of murine fibroblasts.  

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD168 IN INTACT ANIMAL

CD168 receptors mediate glioma cell migration and proliferation.  CD168 is a potential therapeutic target in the treatment of acute myeloid leukemias and other CD168-expressing malignancies.  Increased overall CD168 expression and an increase in the ratio isoform lacking exon 4 to full length CD168 are indicators of disease progression and a poor prognosis for multiple myeloma patients.  Hyper-expression correlates with a poor prognosis for colorectal, stomach and breast cancer patients.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD168: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD168: No information.

ADDITIONAL INSIGHTS

CD168 was initially identified as a 56 kDa-58 kDa HA-binding protein in the supernatant of mouse fibroblasts and fibrosarcoma cell lines.  This protein was used to raise a polyclonal antibody that was found to recognize cell surface molecules and used to isolate a cDNA encoding a 52 kDa polypeptide.  Antibodies raised against this cDNA product were observed to recognize numerous cell surface proteins with a Mr range of 52 kDa-125 kDa presumed to be different isoforms of CD168.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3161O75330
MouseAJ005919-005924
Antibodies

Revised June 25, 2008


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