Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling
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Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. / Huber, Tobias B; Hartleben, Björn; Kim, Jeong; Schmidts, Miriam; Schermer, Bernhard; Keil, Alexander; Egger, Lotti; Lecha, Rachel L; Borner, Christoph; Pavenstädt, Hermann; Shaw, Andrey S; Walz, Gerd; Benzing, Thomas.
In: MOL CELL BIOL, Vol. 23, No. 14, 07.2003, p. 4917-28.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling
AU - Huber, Tobias B
AU - Hartleben, Björn
AU - Kim, Jeong
AU - Schmidts, Miriam
AU - Schermer, Bernhard
AU - Keil, Alexander
AU - Egger, Lotti
AU - Lecha, Rachel L
AU - Borner, Christoph
AU - Pavenstädt, Hermann
AU - Shaw, Andrey S
AU - Walz, Gerd
AU - Benzing, Thomas
PY - 2003/7
Y1 - 2003/7
N2 - Mutations of NPHS1 or NPHS2, the genes encoding nephrin and podocin, as well as the targeted disruption of CD2-associated protein (CD2AP), lead to heavy proteinuria, suggesting that all three proteins are essential for the integrity of glomerular podocytes, the visceral glomerular epithelial cells of the kidney. It has been speculated that these proteins participate in common signaling pathways; however, it has remained unclear which signaling proteins are actually recruited by the slit diaphragm protein complex in vivo. We demonstrate that both nephrin and CD2AP interact with the p85 regulatory subunit of phosphoinositide 3-OH kinase (PI3K) in vivo, recruit PI3K to the plasma membrane, and, together with podocin, stimulate PI3K-dependent AKT signaling in podocytes. Using two-dimensional gel analysis in combination with a phosphoserine-specific antiserum, we demonstrate that the nephrin-induced AKT mediates phosphorylation of several target proteins in podocytes. One such target is Bad; its phosphorylation and inactivation by 14-3-3 protects podocytes against detachment-induced cell death, suggesting that the nephrin-CD2AP-mediated AKT activity can regulate complex biological programs. Our findings reveal a novel role for the slit diaphragm proteins nephrin, CD2AP, and podocin and demonstrate that these three proteins, in addition to their structural functions, initiate PI3K/AKT-dependent signal transduction in glomerular podocytes.
AB - Mutations of NPHS1 or NPHS2, the genes encoding nephrin and podocin, as well as the targeted disruption of CD2-associated protein (CD2AP), lead to heavy proteinuria, suggesting that all three proteins are essential for the integrity of glomerular podocytes, the visceral glomerular epithelial cells of the kidney. It has been speculated that these proteins participate in common signaling pathways; however, it has remained unclear which signaling proteins are actually recruited by the slit diaphragm protein complex in vivo. We demonstrate that both nephrin and CD2AP interact with the p85 regulatory subunit of phosphoinositide 3-OH kinase (PI3K) in vivo, recruit PI3K to the plasma membrane, and, together with podocin, stimulate PI3K-dependent AKT signaling in podocytes. Using two-dimensional gel analysis in combination with a phosphoserine-specific antiserum, we demonstrate that the nephrin-induced AKT mediates phosphorylation of several target proteins in podocytes. One such target is Bad; its phosphorylation and inactivation by 14-3-3 protects podocytes against detachment-induced cell death, suggesting that the nephrin-CD2AP-mediated AKT activity can regulate complex biological programs. Our findings reveal a novel role for the slit diaphragm proteins nephrin, CD2AP, and podocin and demonstrate that these three proteins, in addition to their structural functions, initiate PI3K/AKT-dependent signal transduction in glomerular podocytes.
KW - 14-3-3 Proteins
KW - Adaptor Proteins, Signal Transducing
KW - Animals
KW - Carrier Proteins
KW - Cell Line
KW - Cell Membrane
KW - Cytoskeletal Proteins
KW - Dogs
KW - Humans
KW - Intracellular Signaling Peptides and Proteins
KW - Kidney
KW - Membrane Proteins
KW - Mice
KW - Phosphatidylinositol 3-Kinases
KW - Phosphorylation
KW - Protein Subunits
KW - Protein-Serine-Threonine Kinases
KW - Proteins
KW - Proto-Oncogene Proteins
KW - Proto-Oncogene Proteins c-akt
KW - Signal Transduction
KW - Tyrosine 3-Monooxygenase
KW - bcl-Associated Death Protein
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
M3 - SCORING: Journal article
C2 - 12832477
VL - 23
SP - 4917
EP - 4928
JO - MOL CELL BIOL
JF - MOL CELL BIOL
SN - 0270-7306
IS - 14
ER -