Extracellular CD44 ligands (non-hyaluronan)

Extracellular CD44 ligands encompass a diverse group of molecules, excluding hyaluronan, that interact with the CD44 cell-surface glycoprotein to modulate various cellular processes. Key members of this group include osteopontin, collagen, fibronectin, laminin, and certain matrix metalloproteinases (MMPs), as well as growth factors like hepatocyte growth factor (HGF) (PMID: 11533654, 10449371). These ligands bind to different domains of CD44, often facilitated by specific post-translational modifications or alternative splicing of the CD44 gene, to trigger intracellular signaling pathways such as PI3K/Akt and MAPK (PMID: 11412150). In pathological contexts, these interactions are critical for tumor progression, metastasis, and the maintenance of cancer stem cells, as well as the recruitment of inflammatory cells in autoimmune diseases (PMID: 15322171). For instance, osteopontin binding to CD44 is a well-documented driver of epithelial-mesenchymal transition and chemoresistance in various cancers (PMID: 24297205). Therapeutic strategies targeting these ligands or their binding sites on CD44 aim to disrupt these pro-survival and migratory signals. However, the ubiquitous expression of CD44 across various tissues presents significant challenges for achieving high therapeutic indices and avoiding systemic toxicities, as seen in clinical trials with anti-CD44 antibodies (PMID: 25082054).

Other names

Non-hyaluronan CD44 ligandsCD44-binding proteinsExtracellular matrix CD44 ligands

Competitive inhibition of ligand binding to the CD44 receptor, neutralization of extracellular ligands to prevent receptor activation, and disruption of CD44-mediated cell-matrix interactions.