Insideoutsignaalointi

Insideoutsignaalointi, or inside-out signaling, is a form of cellular signaling in which intracellular cues regulate the activity or affinity of transmembrane receptors, notably integrins, thereby increasing their binding to extracellular ligands. This is in contrast to outside-in signaling, where ligand binding initiates intracellular responses. The concept is widely used in cell biology to describe how cells control adhesion and signaling through receptor activation from within.

Mechanism: In integrins, intracellular signals driven by receptors such as G protein-coupled receptors or chemokine receptors activate the small GTPase Rap1. Rap1, together with effectors like RIAM, promotes recruitment of the cytoskeletal linker proteins talin-1 and kindlin-3 to the β-integrin cytoplasmic tail. This interaction causes separation of the integrin tails and induces a conformational change that shifts the extracellular domain to a high-affinity state, enabling ligands to bind more readily.

Examples and roles: In platelets, inside-out signaling activates αIIbβ3 (GPIIb/IIIa) to bind fibrinogen and von Willebrand factor, enabling platelet aggregation and clot formation. In leukocytes and other cells, inside-out signaling regulates adhesion receptors such as β2 integrins, controlling adhesion to endothelium and subsequent migration. The process is essential for hemostasis, immune cell trafficking, and tissue repair.

Clinical relevance: Defects in inside-out signaling can lead to bleeding disorders or immune dysfunction. For example, impaired kindlin-3 function disrupts integrin activation in platelets and leukocytes, contributing to conditions like leukocyte adhesion deficiency. Pharmacological modulation of integrin activation has therapeutic potential in thrombosis and inflammatory diseases.

Research and scope: Inside-out signaling remains a central concept in integrin biology and cell adhesion. While best characterized for integrins, the framework applies to other receptor systems where intracellular cues modulate receptor affinity or avidity, and it continues to be an active area of investigation.