CD44 is a single-chain transmembrane receptor that exists in multiple forms due to alternative mRNA splicing and post-translational modifications. CD44 is the main cell surface receptor of hyaluronan as well as other extracellular matrix molecules, cytokines, and growth factors that play important roles in physiological processes (such as hematopoiesis and lymphocyte homing) and the progression of various diseases, the predominant one being cancer. Currently, CD44 is an established cancer stem cell marker in several tumors, implying a central functional role in tumor biology. The present review aims to highlight the contribution of the CD44 short cytoplasmic tail, which is devoid of any enzymatic activity, in the extraordinary functional diversity of the receptor. The interactions of CD44 with cytoskeletal proteins through specific structural motifs within its intracellular domain drives cytoskeleton rearrangements and affects the distribution of organelles and transport of molecules. Moreover, the CD44 intracellular domain specifically interacts with various cytoplasmic effectors regulating cell-trafficking machinery, signal transduction pathways, the transcriptome, and vital cell metabolic pathways. Understanding the cell type- and context-specificity of these interactions may unravel the high complexity of CD44 functions and lead to novel improved therapeutic interventions.
CD44是一种单链跨膜受体，由于选择性mRNA剪接和翻译后修饰而存在多种形式。作为透明质酸及其他细胞外基质分子、细胞因子和生长因子的主要细胞表面受体，CD44在生理过程（如造血和淋巴细胞归巢）及多种疾病（尤以癌症为主）进展中发挥重要作用。目前CD44已被确立为多种肿瘤的癌症干细胞标志物，提示其在肿瘤生物学中的核心功能作用。本综述旨在重点阐述CD44短胞质尾端（该结构域不具备任何酶活性）对该受体功能多样性的关键贡献。CD44通过其胞内结构域中的特定基序与细胞骨架蛋白相互作用，驱动细胞骨架重排并影响细胞器分布及分子运输。此外，CD44胞内结构域特异性结合多种胞质效应因子，调控细胞运输机制、信号转导通路、转录组及关键细胞代谢途径。深入理解这些相互作用的细胞类型特异性和环境依赖性，或将揭示CD44功能的高度复杂性，并为开发新型优化治疗策略提供方向。
肿瘤(癌症)患者之家