SLIT2/ROBO2 signaling pathway inhibits nonmuscle myosin IIA activity and destabilizes kidney podocyte adhesion

• DOI: 10.1172/jci.insight.86934
• Publication Date: 2016-11-16T21:25:35Z
• Authors: Xueping Fan; Hongying Yang; Sudhir Kumar; Kathleen E. Tumelty; Anna Pisarek-Horo...; Hila Milo Rasouly; Richa Sharma; Stefanie Chan; Edyta Tyminski; Michael Shamashkin; Mostafa Belghasem; Joel M. Henderson; Anthony J. Coyle; David J. Salant; Stephen P. Berasi; Weining Lu
• Keywords: Mice, Knockout; 0303 health sciences; Podocytes; Nonmuscle Myosin Type IIA; GTPase-Activating Proteins; Nerve Tissue Proteins; Kidney; Mice; 03 medical and health sciences; Cell Movement; Animals; Intercellular Signaling Peptides and Proteins; Receptors, Immunologic; Signal Transduction

The repulsive guidance cue SLIT2 and its receptor ROBO2 are required for kidney development podocyte foot process structure, but the SLIT2/ROBO2 signaling mechanism regulating function is not known. Here we report that a potentially novel pathway consisting of SLIT/ROBO Rho GTPase activating protein 1 (SRGAP1) nonmuscle myosin IIA (NMIIA) regulates adhesion downstream ROBO2. We found II regulatory light chain (MRLC), subunit NMIIA, interacts directly with SRGAP1 forms complex ROBO2/SRGAP1/NMIIA in presence SLIT2. Immunostaining demonstrated colocalized on basal surface podocytes. In addition, stimulation inhibits NMIIA activity, decreases focal formation, reduces attachment to collagen. vivo studies further showed podocyte-specific knockout Robo2 protects mice from hypertension-induced detachment albuminuria also partially rescues podocyte-loss phenotype Myh9 mice. Thus, have identified SLIT2/ROBO2/SRGAP1/NMIIA as podocytes, which may play role attachment. Our findings suggest might be therapeutic target diseases associated loss.