TbetaRI independently activates Smad- and CD2AP-dependent pathways in podocytes.
TGF-beta regulates differentiation, growth, and apoptosis of podocytes and mediates podocyte depletion in glomerulosclerosis. TGF-beta promotes proapoptotic signaling mediated by Smad3 but also activates prosurvival pathways such as phosphoinositide-3 kinase (PI3K)/AKT; the latter requires the CD2-associated adaptor protein (CD2AP) in podocytes. Whether the opposing activities mediated by Smad proteins and CD2AP involve molecular cross-talk is unknown. Here, we report that CD2AP-dependent early activation of the antiapoptotic PI3K/AKT pathway does not require TGF-beta receptor-regulated Smad2 and Smad3. We found that the C-terminal region of CD2AP interacts directly with the cytoplasmic tail of the TGF-beta receptor type I (TbetaRI) in a kinase-dependent manner and that the interaction between the TbetaRI and the p85 subunit of PI3K requires CD2AP. Consistent with the proapoptotic function of Smad signaling, Smad2/3-deficient podocytes were hyperproliferative and resistant to TGF-beta-induced growth inhibition and apoptosis. In contrast, CD2AP-deficient cells were hypoproliferative and hypersensitive to TGF-beta-induced apoptosis. In vivo, to determine the effects of reduced Smad3 or CD2AP gene dosage on podocyte apoptosis and proteinuria characteristic of TGF-beta1 transgenic mice, we generated TGF-beta1 transgenic mice deficient for Smad3 or heterozygous for CD2AP. Smad3 deficiency ameliorated podocyte apoptosis, and CD2AP heterozygosity increased both podocyte apoptosis and proteinuria. These data define distinct canonical (Smad) and noncanonical (CD2AP/PI3K/AKT) pathways that arise from direct, independent interactions with the TbetaRI and that mediate opposing signals for podocyte death or survival.
Xavier
Sandhya
S
Division of Nephrology, Department of Medicine, Charles R Bronfman Institute for Personalized Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Niranjan
Thiruvur
T
Krick
Stefanie
S
Zhang
Taoran
T
Ju
Wenjun
W
Shaw
Andrey S
AS
Schiffer
Mario
M
Böttinger
Erwin P
EP
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000502:physiology*; D007668:Kidney / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D050199:Podocytes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011507:Proteinuria / Q000209:etiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D012598:Sclerosis; D015398:Signal Transduction; D051899:Smad2 Protein / Q000502:physiology*; D051900:Smad3 Protein / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003598:Cytoskeletal Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; C114545:CD2-associated protein; C493957:Cdkn1a protein, mouse; C497783:Smad2 protein, mouse; C497791:Smad3 protein, mouse
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