A novel role for the adaptor molecule CD2-associated protein in transforming growth factor-beta-induced apoptosis.
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.
Schiffer
Mario
M
Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10461, USA.
Mundel
Peter
P
Shaw
Andrey S
AS
Böttinger
Erwin P
EP
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003598:Cytoskeletal Proteins; D015536:Down-Regulation; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D007328:Insulin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D007328:Insulin; D011506:Proteins; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases