CD44, a non-kinase cell surface transmembrane glycoprotein, has diverse functions. It plays crucial roles in normal cell physiological activities like cell proliferation, adhesion, and migration, and is also involved in pathological activities in cancer cells such as angiogenesis, inflammation, and cytoskeleton rearrangement [1,2]. CD44 regularly undergoes alternative splicing, generating standard (CD44s) and variant (CD44v) isoforms. Its interaction with ligands like hyaluronic acid (HA), osteopontin (OPN), and matrix metalloproteinases (MMPs) drives numerous cancer-associated signaling pathways [1].

In vascular endothelial cells (VECs), CD44 was identified to play a crucial role 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. Endothelium-specific CD44ICD knock-in mice are shorter-lived, with VECs showing obvious premature ageing characteristics associated with decreased basal autophagy, while CD44 knockdown ameliorates age-associated phenotypes in VECs [3].

In conclusion, CD44 is a multifunctional molecule involved in various biological processes and diseases. Its role in cancer progression, metabolism, and vascular ageing has been demonstrated through studies. The findings from gene-modified mouse models, such as the CD44ICD knock-in and CD44 knockdown models, have provided insights into its function in specific disease areas, especially in understanding the mechanisms of vascular ageing and its potential as a therapeutic target in related diseases.

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. 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/