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All rights reserved. http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE#_6 http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/version 1.4 http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE#_5 http://www.w3.org/ns/prov#value CD2-associated protein (CD2AP) is an adaptor molecule involved in T cell receptor signaling and podocyte homeostasis. CD2AP-deficient mice develop nephrotic syndrome and renal failure caused by glomerulosclerosis. Here we report that increased transforming growth factor-beta1 (TGF-beta1) expression and apoptosis were present in podocytes at the onset of albuminuria and were followed by depletion of podocytes associated with progressive focal-segmental glomerulosclerosis in CD2AP-/- mice. Conditionally immortalized podocytes derived from CD2AP-/- mice were more susceptible to TGF-beta-induced apoptosis compared with CD2AP+/+ podocytes. Reconstitution of CD2AP rescued CD2AP-/- podocytes from TGF-beta-induced apoptosis. CD2AP was required for early activation of anti-apoptotic phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase 1/2 by TGF-beta. In contrast, activation of pro-apoptotic p38 MAPK by TGF-beta was accelerated and enhanced in the absence of CD2AP. CD2AP was not required for PI3K/AKT activation by insulin and epidermal growth factor, indicating that CD2AP is a selective mediator of anti-apoptotic TGF-beta signaling. In summary, we identified CD2AP as a novel mediator for selective activation of survival pathways and repression of apoptosis signaling by TGF-beta in podocytes. Together, our in vitro and in vivo findings suggest that TGF-beta-induced podocyte apoptosis is an early pathomechanism in mice developing focal-segmental glomerulosclerosis associated with functional impairment of CD2AP. http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE#_5 http://www.w3.org/ns/prov#wasQuotedFrom http://www.ncbi.nlm.nih.gov/pubmed/15213232 http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE#_6 http://www.w3.org/2000/01/rdf-schema#label Selventa http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE#assertion http://www.w3.org/ns/prov#hadPrimarySource http://www.ncbi.nlm.nih.gov/pubmed/15213232 http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE#_5 http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE#pubinfo http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE http://purl.org/dc/terms/created 2014-07-03T14:30:25.235+02:00 http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE http://purl.org/pav/createdBy http://orcid.org/0000-0001-6818-334X http://www.tkuhn.ch/bel2nanopub/RAfMXBGXiVdXy-HTrhYhjvUq8F3gDAtE7mq79avhVPWPE http://purl.org/pav/createdBy http://orcid.org/0000-0002-1267-0234