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.