Lipid–Protein Interplay in the Regulation of Receptor Tyrosine Kinases

Receptor tyrosine kinases (RTKs), a class of membrane proteins involved in several physiological processes such as growth, survival, angiogenesis, and differentiation, are profoundly influenced by the microenvironment, particularly by surrounding lipids. Lipids coordinate RTK life cycle at multiple steps. First, receptor lipidation is a key post-translational modification for receptor-targeting localization. Then, RTK dimerization and activation are regulated by membrane-enriched lipids like phosphatidylserine and phosphoinositides, gangliosides, and Cholesterol, which directly engage RTK juxtamembrane domain or cytoplasmic tail. Eventually, lipids spatially organize RTK signaling within Cholesterol- and sphingolipid-enriched membrane microdomains. These membrane rafts act as dynamic "signalosomes" coordinating receptor clustering, endocytosis, and recycling. Perturbations in lipid composition remodel raft architecture and alter RTK behavior, contributing to pathological conditions such as cancer, metabolic, and neurodegenerative disorders. Emerging lipid-targeted therapies offer a promising way to enhance RTK-directed therapies. This review aims to explore how specific lipid species and membrane domains modulate RTK activation, clustering, and endocytic recycling. By bridging biochemical and pathological perspectives, we discuss how membrane lipid composition reshapes RTK signaling in physiology and pathology, pointing to emerging opportunities for lipid-focused therapeutic modulation.