Trans-interaction of nephrin and Neph1/Neph3 induces cell adhesion that associates with decreased tyrosine phosphorylation of nephrin

Eija Heikkilä , Mervi Ristola , Marika Havana , Nina Jones , Harry Holthöfer , Sanna Lehtonen (1)

1 Department of Pathology [Helsinki]

Slit diaphragms are specialized junctions between glomerular epithelial cells (podocytes) that are crucial for glomerular ultrafiltration. Ig superfamily members nephrin and Neph1 are essential components of the slit diaphragm, whereas the role of Neph1 homologue Neph3 in the slit diaphragm is unknown. Here we show that Neph3 homodimerizes and heterodimerizes with nephrin and Neph1. We further investigated whether these interactions play a role in cell adhesion by using mouse L fibroblasts that lack endogenous cell adhesion activity, and found that Neph1 and Neph3 are able to induce cell adhesion alone whereas nephrin needs to trans-interact with Neph1 or Neph3 in order to promote formation of cell-cell contacts. Tyrosine phosphorylation of nephrin was down-regulated after nephrin trans-interacted with either Neph1 or Neph3 leading to formation of cell-cell contacts. We further found that the expression of Neph3 was increased in nephrin deficient mouse kidneys suggesting that Neph3 may participate in the formation of tight-junction-like structures observed in nephrin deficient podocytes. Our findings show that nephrin and Neph1 or Neph3 trans-interactions promote cell contact formation suggesting that they could function together also in the slit diaphragm assembly, and when nephrin is absent, participate in the formation of altered junctional complexes between podocyte foot processes.

Mots clés: Life Sciences

Eija Heikkilä, Mervi Ristola, Marika Havana, Nina Jones, Harry Holthöfer, et al.. Trans-interaction of nephrin and Neph1/Neph3 induces cell adhesion that associates with decreased tyrosine phosphorylation of nephrin. Biochemical Journal, 2011, 435 (3), pp.619-628. ⟨10.1042/BJ20101599⟩. ⟨hal-00586463⟩