title: Trans-interaction of nephrin and Neph1/Neph3 induces cell adhesion that associates with decreased tyrosine phosphorylation of nephrin.
abstract: Slit diaphragms are specialized junctions between glomerular epithelial cells (podocytes) that are crucial for glomerular ultrafiltration. The 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. In the present paper 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 podocytes. The findings of the present paper show that nephrin and Neph1 or Neph3 trans-interactions promote cell-contact formation, suggesting that they may also function together in slit diaphragm assembly.
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Heikkilä
authors.forename: Mervi
authors.initials: M
authors.lastname: Ristola
authors.forename: Marika
authors.initials: M
authors.lastname: Havana
authors.forename: Nina
authors.initials: N
authors.lastname: Jones
authors.forename: Harry
authors.initials: H
authors.lastname: Holthöfer
authors.forename: Sanna
authors.initials: S
authors.lastname: Lehtonen
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051381:Rats; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D007136:Immunoglobulins; C482646:KIRREL2 protein, human; C486606:Kirrel1 protein, mouse; D008565:Membrane Proteins; C546601:Neph3 protein, mouse; C113267:nephrin; D014443:Tyrosine