CD44

Official Full Name

CD44 molecule (IN blood group)

Organism

Homo sapiens

GeneID

960

Background

The protein encoded by this gene is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration. It is a receptor for hyaluronic acid (HA) and can also interact with other ligands, such as osteopontin, collagens, and matrix metalloproteinases (MMPs). This protein participates in a wide variety of cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis. Transcripts for this gene undergo complex alternative splicing that results in many functionally distinct 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. [provided by RefSeq, Jul 2008]

Synonyms

IN; LHR; MC56; MDU2; MDU3; MIC4; Pgp1; CDW44; CSPG8; H-CAM; HCELL; ECM-III; HUTCH-1; HUTCH-I; ECMR-III; Hermes-1;

Protein Sequence

MDKFWWHAAWGLCLVPLSLAQIDLNITCRFAGVFHVEKNGRYSISRTEAADLCKAFNSTLPTMAQMEKALSIGFETCRYGFIEGHVVIPRIHPNSICAANNTGVYILTSNTSQYDTYCFNASAPPEEDCTSVTDLPNAFDGPITITIVNRDGTRYVQKGEYRTNPEDIYPSNPTDDDVSSGSSSERSSTSGGYIFYTFSTVHPIPDEDSPWITDSTDRIPATTLMSTSATATETATKRQETWDWFSWLFLPSESKNHLHTTTQMAGTSSNTISAGWEPNEENEDERDRHLSFSGSGIDDDEDFISSTISTTPRAFDHTKQNQDWTQWNPSHSNPEVLLQTTTRMTDVDRNGTTAYEGNWNPEAHPPLIHHEHHEEEETPHSTSTIQATPSSTTEETATQKEQWFGNRWHEGYRQTPKEDSHSTTGTAAASAHTSHPMQGRTTPSPEDSSWTDFFNPISHPMGRGHQAGRRMDMDSSHSITLQPTANPNTGLVEDLDRTGPLSMTTQQSNSQSFSTSHEGLEEDKDHPTTSTLTSSNRNDVTGGRRDPNHSEGSTTLLEGYTSHYPHTKESRTFIPVTSAKTGSFGVTAVTVGDSNSNVNRSLSGDQDTFHPSGGSHTTHGSESDGHSHGSQEGGANTTSGPIRTPQIPEWLIILASLLALALILAVCIAVNSRRRCGQKKKLVINSGNGAVEDRKPSGLNGEASKSQEMVHLVNKESSETPDQFMTADETRNLQNVDMKIGV

Open

Disease

Ovarian cancer, Retinopathy, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

1 +

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Detailed Information

Crucially important in cell-cell contacts, adhesion, migration, and signaling, the CD44 gene codes a cell surface glycoprotein. Apart from interacting with other ligands like osteopontin, collagens, and matrix metalloproteinases (MMPs), CD44 is well-known to be a receptor for hyaluronic acid (HA). Among the many biological activities this gene participates in are lymphocyte activation, homing, hematopoiesis, and tumor metastases. Although the full-length structure of certain variations has not yet been established, the CD44 transcripts undergo extensive alternative splicing producing numerous different isoforms. The structural and functional adaptability of CD44, which could be linked with tumor metastases, depends on this splicing variety.

General Characteristics of CD44

Encoded by a single gene at chromosomal location 11p13, CD44, often referred to as P-glycoprotein 1, is a transmembrane glycoprotein Widely expressed throughout many tissues in the body, including the central nervous system, lung, and epidermis, the protein with a molecular weight of 85–200 kDa is Comprising exons 1–5 and 16–20, spliced together, the highly conserved standard form of CD44 (sCD44) has a molecular weight of around 85–90 kDa.

The extracellular domain (ectodomain), the transmembrane domain, and the cytoplasmic domain (ICD) define three key domains for CD44. The extracellular domain interacts with elements of the extracellular matrix (ECM), including growth hormones, HA, and collagen, and HA, Guiding lymphocyte motility and homing, the transmembrane domain helps interactions with co-factor and adaptor proteins. Though small, the cytoplasmic domain has been proven to be important for nuclear localization and control of transcription.

Isoforms of CD44

Different isoforms are produced by the CD44 gene from various exons inserted into the extracellular domain. From splicing exons 6–15 at various positions between exons 5 and 16 of the normal CD44 form, these variant isoforms (CD44v) result The expression of certain CD44 isoforms has been connected to the development of some malignant tumors. For instance, although in colorectal cancer CD44v6 expression corresponds with tumor growth and prognosis, in pancreatic cancer bigger isoforms such as CD44v8-10 are commonly overexpressed. Particularly the CD44v6 isoform is now a well-known indicator of colorectal cancer tumor development.

Moreover, CD44v6 expression is linked to cancer stem cells, suggesting its important part in tumor development. These isoforms could also improve cell survival, adhesion, and migration, therefore helping the metastatic process in cancer.

Figure 1 illustrates the cleavage and functional role of CD44 in cancer cell dissemination and metastasis, highlighting its impact on gene activation for metastasis and cell survival. Figure 1. CD44 Transmembrane Receptor Function. (Senbanjo LT, et al., 2017)

CD44 in Normal and Tumor Cells

In normal tissues, CD44 plays a key function in regulating hyaluronic acid metabolism, activating lymphocytes, and cytokine release. However, the absence of CD44 might throw off these systems, therefore affecting cell growth and healing of wounds. For prostate cancer, for instance, benign cells express variant CD44 (CD44v), but neoplastic cells usually exhibit the normal CD44 isoform.

Unusual expression of CD44—including heterogeneous expression of CD44 isoforms—has been noted in breast cancer. Understanding tumor spread depends critically on the dynamic character of CD44 expression and its isoforms in cancer cells.

CD44 Receptor-Ligand Interactions

With a range of ligands, CD44 interacts most famously with hyaluronic acid (HA). For CD44's many biological purposes, especially in cancer cell migration and proliferation, this connection is very essential. A glycosaminoglycan component of the extracellular matrix, HA hooks to CD44 to initiate cytoskeleton and matrix metalloproteinases (MMPs) signaling pathways. Tumor development and metastases depend on these signaling events.

Apart from HA, CD44 interacts additionally with a protein present in many tissues called osteopontin (OPN). OPN's binding to CD44 enhances cell migration and invasion. Research has shown that the formation and spread of invasive metastatic malignancies, including prostate cancer, depends on the interaction between CD44 and OPN.

Tumor-Specific CD44 Expression

While variant isoforms are produced in certain epithelial cells, the expression of CD44 isoforms is not homogeneous across all tissues; the normal CD44 isoform is expressed ubiquitously. Keratinocytes, macrophages, and certain epithelial cells, for example, express CD44v isoforms, which are also present during many phases of tissue development. Significantly, the expression of these variant isoforms has been correlated to tumor metastatic potential. Research on prostate cancer cells reveals that the survival and adhesion characteristics of cancer cells increase when conventional CD44 is changed to CD44v6, therefore improving their metastatic potential.

References:

Senbanjo LT, Chellaiah MA. CD44: A Multifunctional Cell Surface Adhesion Receptor Is a Regulator of Progression and Metastasis of Cancer Cells. Front Cell Dev Biol. 2017;5:18.
Xu H, Niu M, Yuan X, Wu K, Liu A. CD44 as a tumor biomarker and therapeutic target. Exp Hematol Oncol. 2020;9(1):36.
Xu Y, Bai Z, Lan T, et al. CD44 and its implication in neoplastic diseases. MedComm (2020). 2024;5(6):e554.

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