Crk1/2 and CrkL form a hetero-oligomer and functionally complement each other during podocyte morphogenesis.
Activation of the slit diaphragm protein nephrin induces actin cytoskeletal remodeling, resulting in lamellipodia formation in podocytes in vitro in a phosphatidylinositol-3 kinase-, focal adhesion kinase-, Cas-, and Crk1/2-dependent fashion. In mice, podocyte-specific deletion of Crk1/2 prevents or attenuates foot process effacement in two models of podocyte injury. This suggests that cellular mechanisms governing lamellipodial protrusion in vitro are similar to those in vivo during foot process effacement. As Crk1/2-null mice developed and aged normally, we tested whether the Crk1/2 paralog, CrkL, functionally complements Crk1/2 in a podocyte-specific context. Podocyte-specific CrkL-null mice, like podocyte-specific Crk1/2-null mice, developed and aged normally but were protected from protamine sulfate-induced foot process effacement. Simultaneous podocyte-specific deletion of Crk1/2 and CrkL resulted in albuminuria detected by 6 weeks postpartum and associated with altered podocyte process architecture. Nephrin-induced lamellipodia formation in podocytes in vitro was CrkL-dependent. CrkL formed a hetero-oligomer with Crk2 and, like Crk2, was recruited to tyrosine phosphorylated nephrin. Thus, Crk1/2 and CrkL are physically linked, functionally complement each other during podocyte foot process spreading, and together are required for developing typical foot process architecture.
Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.|Medizinische Klinik und Poliklinik D, Universitätsklinikum Münster, Münster, Germany.
Britta
B
George
Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
Qingfeng
Q
Fan
Medizinische Klinik und Poliklinik D, Universitätsklinikum Münster, Münster, Germany.
Christopher P
CP
Dlugos
Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
Abdulsalam A
AA
Soofi
Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
Jidong
J
Zhang
Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
Rakesh
R
Verma
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA.
Tae-Ju
TJ
Park
Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
Hetty
H
Wong
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA.
Tom
T
Curran
Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
Deepak
D
Nihalani
Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.|Department of Veterans Affair, Philadelphia, PA, USA.
Lawrence B
LB
Holzman
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000419:Albuminuria / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D009024:Morphogenesis; D046912:Multiprotein Complexes; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D011479:Protamines / Q000633:toxicity; D050737:Proto-Oncogene Proteins c-crk / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011479:Protamines; D050737:Proto-Oncogene Proteins c-crk; C113267:nephrin