TbetaRI independently activates Smad- and CD2AP-dependent pathways in podocytes.
Authors Xavier S, Niranjan T, Krick S, Zhang T, Ju W, Shaw AS, Schiffer M, Bottinger EP
Submitted By Erwin Bottinger on 6/9/2015
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2009
Date Published 10/1/2009
Volume : Pages 20 : 2127 - 2137
PubMed Reference 19679673
Abstract 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.


Investigators with authorship
NameInstitution
Erwin BottingerMount Sinai School of Medicine

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