Figure 3 Integrative signalling networks enable interactions

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Figure 3 Integrative signalling networks enable interactions between podocyte focal adhesions, the slit diaphragm and actin dynamics Figure 3 | Integrative signalling networks enable interactions between podocyte focal adhesions, the slit diaphragm and actin dynamics. At the interface with the glomerular basement membrane, podocyte foot processes express integrins, dystroglycans and syndecans, which generate high-affinity adhesions to the extracellular matrix. Cytoplasmic proteins including integrin-linked kinase (ILK), focal adhesion kinase (FAK) and α-actinin-4, form large macromolecular assemblies with integrins, termed focal adhesions, that bear the podocyte structural load and relay intracellular signalling pathways by interacting with the cytoskeletal network. Neighbouring foot processes are bridged by slit diaphragms, specialized intracellular junctions with filtration slits formed by nephrin and nephrin-like protein 1 (NEPH1). At the slit diaphragm, podocin, short transient receptor potential channel 6 (TRPC6) and CD2-associated protein (CD2AP) provide structural and functional support for the filtration barrier and participate in signalling pathways by interacting with the components of the actin cytoskeleton. The arrows depict the pathways through which slit diaphragm components modulate cytoskeletal dynamics via the small GTPases, transforming protein RhoA (RhoA), ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 homologue (Cdc42). α3, integrin α3; Arp2/3, actin-related protein 2/3; β1, integrin β1; BRAF, serine/threonine-protein kinase B-raf; Ca2+, calcium; CAPZ, F-actin capping protein; DAG, diacylglycerol; ER, endoplasmic reticulum; F-actin, filamentous actin; Fyn, tyrosine-protein kinase Fyn; IP3, inositol 1,4,5-trisphosphate; IQGAP1, Iq-motif containing GTPase-activating protein 1; NHERF, Na+/H+ exchange regulatory cofactor; N-WASP, neural Wiskott–Aldrich syndrome protein; PAK, p21-activated kinases; PINCH, particularly interesting new Cys-His protein 1; PIP2, phosphatidylinositol bisphosphate; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLCε1, phospholipase Cε1; PLCγ1, phospholipase Cγ1. Perico, L. et al. (2016) Podocyte–actin dynamics in health and disease Nat. Rev. Nephrol. doi:10.1038/nrneph.2016.127