CD44, a non-kinase cell surface transmembrane glycoprotein, is involved in multiple physiological and pathological processes. It plays essential roles in cell proliferation, adhesion, migration, angiogenesis, inflammation, and cytoskeleton rearrangement in normal and cancer cells [1,2]. CD44 can interact with ligands like hyaluronic acid (HA), osteopontin (OPN), and matrix metalloproteinases (MMPs), driving cancer-associated signaling. The gene undergoes alternative splicing, resulting in standard (CD44s) and variant (CD44v) isoforms [1,3].

In the vascular endothelium, CD44 was found to be crucial in controlling autophagy and ageing. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. An age-dependent increase in CD44 was observed to induce autophagy decline and ageing phenotypes, and CD44 knockdown ameliorated age-associated phenotypes in vascular endothelial cells (VECs). The endothelium-specific CD44ICD knock-in mouse had a shorter lifespan with VECs showing premature ageing characteristics due to decreased basal autophagy [4].

In conclusion, CD44 is a multifunctional molecule involved in various biological functions. Its role in autophagy and ageing in the vascular endothelium, as revealed by the CD44ICD knock-in mouse model, provides insights into the molecular mechanisms of vascular senescence and disease. In cancer, CD44 is associated with tumorigenesis, metastasis, and stemness, making it an important clinical target [1,4].

References:

1. Hassn Mesrati, Malak, Syafruddin, Saiful Effendi, Mohtar, M Aiman, Syahir, Amir. 2021. CD44: A Multifunctional Mediator of Cancer Progression. In Biomolecules, 11, . doi:10.3390/biom11121850. https://pubmed.ncbi.nlm.nih.gov/34944493/

2. Weng, Xiong, Maxwell-Warburton, Samuel, Hasib, Annie, Ma, Lifeng, Kang, Li. 2022. The membrane receptor CD44: novel insights into metabolism. In Trends in endocrinology and metabolism: TEM, 33, 318-332. doi:10.1016/j.tem.2022.02.002. https://pubmed.ncbi.nlm.nih.gov/35249813/

3. Chen, Chen, Zhao, Shujie, Karnad, Anand, Freeman, James W. 2018. The biology and role of CD44 in cancer progression: therapeutic implications. In Journal of hematology & oncology, 11, 64. doi:10.1186/s13045-018-0605-5. https://pubmed.ncbi.nlm.nih.gov/29747682/

4. Zhang, Lu, Yang, Peichang, Chen, Jingxuan, Jing, Hongjuan, Ma, Shiwei. 2023. CD44 connects autophagy decline and ageing in the vascular endothelium. In Nature communications, 14, 5524. doi:10.1038/s41467-023-41346-y. https://pubmed.ncbi.nlm.nih.gov/37684253/