Hyaluronan (HA) is a glycosaminoglycan that binds to cell surface receptors, such as CD44 and RHAMM, and plays a key role in cell signaling. HA can activate various protein tyrosine and serine/threonine kinases, including Src, HER2/Neu, focal adhesion kinase, protein kinase C, and MAP kinases. These signaling pathways are involved in cell motility, proliferation, migration, and angiogenesis. HA also promotes the expression of cytokines and proteins involved in extracellular matrix remodeling. CD44 is an integral membrane protein that binds to HA and regulates cell adhesion, migration, and signaling. CD44 interacts with tyrosine kinases such as Src and HER2, and activates Rho-like GTPases like RhoA and Rac1, which are involved in cytoskeletal dynamics and cell motility. CD44 also interacts with ankyrin and ERM proteins, which are involved in cytoskeletal organization. RHAMM is another hyaladherin that binds to HA and is involved in signaling through Ras and Src. RHAMM also interacts with the cytoskeleton and kinases, and may function as an adapter protein. RHAMM is involved in cell migration, and its interaction with HA is essential for hyaluronan-mediated signaling. The size of HA can influence its signaling activity. In physiological conditions, HA is a high molecular weight polymer, but following tissue injury, smaller fragments are produced. These fragments can activate signaling pathways and induce inflammatory gene expression. The size of HA may also affect its ability to bind to hyaladherins and activate signaling. Hyaladherins such as CD44 and RHAMM are involved in HA internalization and host response to injury. CD44-deficient mice exhibit abnormalities in hematopoiesis and lymphocyte recirculation, but do not show embryonic lethality, suggesting that other hyaladherins may compensate for the loss of CD44. CD44 is also essential for regulating pathogenesis of host injury in models of tissue injury. In conclusion, HA signaling involves cellular hyaladherins such as CD44 and RHAMM, which are selectively coupled with their particular downstream signaling pathways. The size of HA and the cell background can influence the signaling response. Further studies are needed to clarify the cellular conditions that permit HA-mediated signaling.Hyaluronan (HA) is a glycosaminoglycan that binds to cell surface receptors, such as CD44 and RHAMM, and plays a key role in cell signaling. HA can activate various protein tyrosine and serine/threonine kinases, including Src, HER2/Neu, focal adhesion kinase, protein kinase C, and MAP kinases. These signaling pathways are involved in cell motility, proliferation, migration, and angiogenesis. HA also promotes the expression of cytokines and proteins involved in extracellular matrix remodeling. CD44 is an integral membrane protein that binds to HA and regulates cell adhesion, migration, and signaling. CD44 interacts with tyrosine kinases such as Src and HER2, and activates Rho-like GTPases like RhoA and Rac1, which are involved in cytoskeletal dynamics and cell motility. CD44 also interacts with ankyrin and ERM proteins, which are involved in cytoskeletal organization. RHAMM is another hyaladherin that binds to HA and is involved in signaling through Ras and Src. RHAMM also interacts with the cytoskeleton and kinases, and may function as an adapter protein. RHAMM is involved in cell migration, and its interaction with HA is essential for hyaluronan-mediated signaling. The size of HA can influence its signaling activity. In physiological conditions, HA is a high molecular weight polymer, but following tissue injury, smaller fragments are produced. These fragments can activate signaling pathways and induce inflammatory gene expression. The size of HA may also affect its ability to bind to hyaladherins and activate signaling. Hyaladherins such as CD44 and RHAMM are involved in HA internalization and host response to injury. CD44-deficient mice exhibit abnormalities in hematopoiesis and lymphocyte recirculation, but do not show embryonic lethality, suggesting that other hyaladherins may compensate for the loss of CD44. CD44 is also essential for regulating pathogenesis of host injury in models of tissue injury. In conclusion, HA signaling involves cellular hyaladherins such as CD44 and RHAMM, which are selectively coupled with their particular downstream signaling pathways. The size of HA and the cell background can influence the signaling response. Further studies are needed to clarify the cellular conditions that permit HA-mediated signaling.