CD44 Intracellular Domain: A Long Tale of a Short Tail

SIMPLE SUMMARY: This review is focused on the interactions of the CD44 cytoplasmic tail in order to unravel the high complexity of CD44 functions. CD44 serves as a cell surface receptor for various extracellular matrix molecules, mainly hyaluronan, and messenger molecules, such as growth factors, and has important functions in normal and disease states, the predominant one being cancer. CD44 coordinates both structural and signaling events through its highly conserved intracellular domain. Although short and devoid of any enzymatic activity, the CD44 intracellular domain possesses structural motifs that promote the interactions with cytoplasmic effectors involved in important cellular pathways, including cell trafficking, transcription, and metabolism, which regulate cellular functions like growth, survival, differentiation, stemness, and therapeutic resistance. ABSTRACT: 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.