CD44

The CD44 antigen is a cell-surface is_associated_with::glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 is_associated_with::gene on Chromosome 11. CD44 has been referred to as HCAM (homing is_associated_with::cell adhesion molecule), Pgp-1 (phagocytic is_associated_with::glycoprotein-1), Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.

Tissue distribution and isoforms
CD44 is expressed in a large number of mammalian cell types. The standard isoform, designated CD44s, comprising is_associated_with::exons 1–5 and 16–20 is expressed in most cell types. CD44 splice variants containing variable exons are designated CD44v. Some epithelial cells also express a larger isoform (CD44E), which includes exons v8–10.

Function
CD44 is a receptor for is_associated_with::hyaluronic acid and can also interact with other is_associated_with::ligands, such as is_associated_with::osteopontin, is_associated_with::collagens, and is_associated_with::matrix metalloproteinases (MMPs). CD44 function is controlled by its posttranslational modifications. One critical modification involves discrete sialofucosylations rendering the selectin-binding glycoform of CD44 called HCELL (for Hematopoietic Cell E-selectin/L-selectin Ligand). The HCELL glycoform was originally discovered on human hematopoietic stem cells and leukemic blasts,   and was subsequently identified on cancer cells. HCELL functions as a "bone homing receptor", directing migration of human hematopoietic stem cells and is_associated_with::mesenchymal stem cells to bone marrow. Ex vivo glycan engineering of the surface of live cells has been used to enforce HCELL expression on any cell that expresses CD44. CD44 glycosylation also directly controls its binding capacity to fibrin and immobilized fibrinogen.

This protein participates in a wide variety of cellular functions including is_associated_with::lymphocyte activation, recirculation and homing, is_associated_with::hematopoiesis, and is_associated_with::tumor is_associated_with::metastasis. Transcripts for this is_associated_with::gene undergo complex is_associated_with::alternative splicing that results in many functionally distinct is_associated_with::isoforms; however, the full length nature of some of these variants has not been determined. Alternative splicing is the basis for the structural and functional diversity of this protein, and may be related to tumor metastasis. Splice variants of CD44 on colon cancer cells display sialofucosylated HCELL glycoforms that serve as P-, L-, and E-selectin ligands and fibrin, but not fibrinogen, receptors under hemodynamic flow conditions pertinent to the process of cancer metastasis. CD44 gene transcription is at least in part activated by is_associated_with::beta-catenin and Wnt signalling (also linked to tumour development).

Clinical significance
The protein is a determinant for the is_associated_with::Indian blood group system.


 * CD44, along with is_associated_with::CD25, is used to track early is_associated_with::T cell development in the is_associated_with::thymus.


 * CD44 expression is an indicative marker for effector-memory T-cells. Memory cell proliferation (activation) can also be assayed in vitro with CFSE chemical tagging.

In addition, variations in CD44 are reported as cell surface markers for some breast and prostate is_associated_with::cancer stem cells.In breast cancer research CD44+/CD24- expression is commonly used as a marker for breast CSCs and is used to sort breast cancer cells into a population enriched in cells with stem-like characteristics and has been seen as an indicator of increased survival time in is_associated_with::epithelial is_associated_with::ovarian cancer patients.

Endometrial cells in women with is_associated_with::endometriosis demonstrate increased expression of splice variants of CD44, and increased adherence to peritoneal cells.

CD44 variant is_associated_with::isoforms are also relevant to the progression of head and neck squamous cell carcinoma.

is_associated_with::Monoclonal antibodies against CD44 variants include is_associated_with::bivatuzumab for v6.

CD44 in Cancer
CD44 is a multistructural and multifunctional cell surface molecule involved in cell proliferation, cell differentiation, is_associated_with::cell migration, is_associated_with::angiogenesis, presentation of is_associated_with::cytokines, is_associated_with::chemokines, and growth factors to the corresponding receptors, and docking of is_associated_with::proteases at the is_associated_with::cell membrane, as well as in signaling for cell survival. All these biological properties are essential to the physiological activities of normal cells, but they are also associated with the pathologic activities of is_associated_with::cancer cells. Experiments in animals have shown that targeting of CD44 by antibodies, antisense oligonucleotides, and CD44-soluble proteins markedly reduces the malignant activities of various is_associated_with::neoplasms, stressing the therapeutic potential of anti-CD44 agents. Furthermore, because is_associated_with::alternative splicing and is_associated_with::posttranslational modifications generate many different CD44 sequences, including, perhaps, tumor-specific sequences, the production of anti-CD44 tumor-specific agents may be a realistic therapeutic approach. However, in many cancers (renal cancer and non-Hodgkin's lymphomas are exceptions), a high level of CD44 expression is not always associated with an unfavorable outcome. On the contrary, in some neoplasms CD44 upregulation is associated with a favorable outcome. Additionally, in many cases different research groups analyzing the same neoplastic disease reached contradictory conclusions regarding the correlation between CD44 expression and disease prognosis, possibly due to differences in methodology. These problems must be resolved before applying anti-CD44 therapy to human cancers.

Interactions
CD44 has been shown to interact with:


 * is_associated_with::ARHGEF1,
 * is_associated_with::Ezrin, via is_associated_with::PIP2,
 * is_associated_with::Fibrin and immobilized is_associated_with::fibrinogen.
 * is_associated_with::Fibronectin,
 * is_associated_with::FYN,
 * is_associated_with::Osteopontin
 * is_associated_with::Lck,
 * is_associated_with::Selectins,  and
 * Src.