Complementary Nck1/2 Signaling in Podocytes Controls ?Actinin-4?Mediated Actin Organization, Adhesion, and Basement Membrane Composition

Podocyte detachment is a major contributor to kidney disease progression, yet the mechanisms controlling podocyte adhesion are not well understood. We identified novel roles for Nck1 and Nck2 cytoskeletal adaptor proteins in cell adhesion through regulation of actin bundling at focal adhesions via ?actinin-4. In vivo, loss of Nck1 and/or Nck2 increases basement membrane matrix deposition and renders podocytes more susceptible to damage after injury and with aging. More severe defects are observed with Nck2 deficiency, consistent with identification of distinct effector proteins. The results suggest an essential role for Nck adaptors as molecular hubs integrating multiple actin-based signals to control podocyte adhesion dynamics.