Beyond Integrin Activation: Kindlin-3 as an Organiser of Immune Receptor Signalling

Kindlins are best known for their roles in integrin regulation, but studies across the family have revealed additional functions in receptor trafficking, stability and signalling. In this review, we examine these non-canonical functions with a focus on kindlin-3 and its emerging role in cytokine receptor regulation. Kindlin-3 is the predominant kindlin in haematopoietic cells and is essential for integrin-dependent leukocyte adhesion and platelet function. Beyond these established roles, kindlin-3 participates in bidirectional integrin regulation, promotes integrin clustering and associates with signalling adaptors that couple adhesion to downstream cellular responses. A recent study further reported that kindlin-3 binds interleukin-2 receptor β (IL-2Rβ) through its F0 subdomain and promotes IL-2Rβ retention at the plasma membrane in a manner dependent on the integrin lymphocyte function-associated antigen 1 (LFA-1). Loss of kindlin-3 accelerates IL-2Rβ internalisation; reduces the persistence of interleukin-2 (IL-2)-induced signal transducer and activator of transcription 5 (STAT5), AKT and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation; and increases natural killer cell susceptibility to apoptosis under limiting IL-2 conditions, suggesting a possible role of kindlin-3 in sustaining cytokine responsiveness in immune cells. We further consider structural features and post-translational mechanisms that may influence receptor organisation, including the F3 integrin-binding subdomain, F1 loop, pleckstrin homology domain and phosphorylation of kindlin-3. Finally, we discuss whether related receptor-organising functions extend to interleukin-15 (IL-15) signalling, other kindlin paralogues and distinct tissue contexts. Together, the available evidence broadens the established role of kindlin-3 in immune cells and raises important questions about how kindlins coordinate integrins with other signalling receptors.