Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis.

Hdl Handle:
http://hdl.handle.net/10147/237973
Title:
Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis.
Authors:
Akilesh, Shreeram; Suleiman, Hani; Yu, Haiyang; Stander, M Christine; Lavin, Peter; Gbadegesin, Rasheed; Antignac, Corinne; Pollak, Martin; Kopp, Jeffrey B; Winn, Michelle P; Shaw, Andrey S
Affiliation:
Department of Pathology, Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.
Citation:
Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. 2011, 121 (10):4127-37 J. Clin. Invest.
Journal:
The Journal of clinical investigation
Issue Date:
Oct-2011
URI:
http://hdl.handle.net/10147/237973
DOI:
10.1172/JCI46458
PubMed ID:
21911940
Abstract:
The specialized epithelial cell of the kidney, the podocyte, has a complex actin-based cytoskeleton. Dynamic regulation of this cytoskeleton is required for efficient barrier function of the kidney. Podocytes are a useful cell type to study the control of the actin cytoskeleton in vivo, because disruption of components of the cytoskeleton results in podocyte damage, cell loss, and a prototypic injury response called focal segmental glomerulosclerosis (FSGS). Searching for actin regulatory proteins that are expressed in podocytes, we identified a RhoA-activated Rac1 GTPase-activating protein (Rac1-GAP), Arhgap24, that was upregulated in podocytes as they differentiated, both in vitro and in vivo. Increased levels of active Rac1 and Cdc42 were measured in Arhgap24 knockdown experiments, which influenced podocyte cell shape and membrane dynamics. Consistent with a role for Arhgap24 in normal podocyte functioning in vivo, sequencing of the ARHGAP24 gene in patients with FSGS identified a mutation that impaired its Rac1-GAP activity and was associated with disease in a family with FSGS. Thus, Arhgap24 contributes to the careful balancing of RhoA and Rac1 signaling in podocytes, the disruption of which may lead to kidney disease.
Item Type:
Article
Language:
en
MeSH:
Amino Acid Sequence; Animals; Cell Differentiation; Cell Membrane; Cell Shape; Female; GTPase-Activating Proteins; Gene Knockdown Techniques; Glomerulosclerosis, Focal Segmental; Humans; Male; Mice; Molecular Sequence Data; Mutant Proteins; Neuropeptides; Pedigree; Podocytes; Sequence Homology, Amino Acid; rac GTP-Binding Proteins
ISSN:
1558-8238

Full metadata record

DC FieldValue Language
dc.contributor.authorAkilesh, Shreeramen_GB
dc.contributor.authorSuleiman, Hanien_GB
dc.contributor.authorYu, Haiyangen_GB
dc.contributor.authorStander, M Christineen_GB
dc.contributor.authorLavin, Peteren_GB
dc.contributor.authorGbadegesin, Rasheeden_GB
dc.contributor.authorAntignac, Corinneen_GB
dc.contributor.authorPollak, Martinen_GB
dc.contributor.authorKopp, Jeffrey Ben_GB
dc.contributor.authorWinn, Michelle Pen_GB
dc.contributor.authorShaw, Andrey Sen_GB
dc.date.accessioned2012-08-09T13:22:45Z-
dc.date.available2012-08-09T13:22:45Z-
dc.date.issued2011-10-
dc.identifier.citationArhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. 2011, 121 (10):4127-37 J. Clin. Invest.en_GB
dc.identifier.issn1558-8238-
dc.identifier.pmid21911940-
dc.identifier.doi10.1172/JCI46458-
dc.identifier.urihttp://hdl.handle.net/10147/237973-
dc.description.abstractThe specialized epithelial cell of the kidney, the podocyte, has a complex actin-based cytoskeleton. Dynamic regulation of this cytoskeleton is required for efficient barrier function of the kidney. Podocytes are a useful cell type to study the control of the actin cytoskeleton in vivo, because disruption of components of the cytoskeleton results in podocyte damage, cell loss, and a prototypic injury response called focal segmental glomerulosclerosis (FSGS). Searching for actin regulatory proteins that are expressed in podocytes, we identified a RhoA-activated Rac1 GTPase-activating protein (Rac1-GAP), Arhgap24, that was upregulated in podocytes as they differentiated, both in vitro and in vivo. Increased levels of active Rac1 and Cdc42 were measured in Arhgap24 knockdown experiments, which influenced podocyte cell shape and membrane dynamics. Consistent with a role for Arhgap24 in normal podocyte functioning in vivo, sequencing of the ARHGAP24 gene in patients with FSGS identified a mutation that impaired its Rac1-GAP activity and was associated with disease in a family with FSGS. Thus, Arhgap24 contributes to the careful balancing of RhoA and Rac1 signaling in podocytes, the disruption of which may lead to kidney disease.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of clinical investigationen_GB
dc.subject.meshAmino Acid Sequence-
dc.subject.meshAnimals-
dc.subject.meshCell Differentiation-
dc.subject.meshCell Membrane-
dc.subject.meshCell Shape-
dc.subject.meshFemale-
dc.subject.meshGTPase-Activating Proteins-
dc.subject.meshGene Knockdown Techniques-
dc.subject.meshGlomerulosclerosis, Focal Segmental-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshMutant Proteins-
dc.subject.meshNeuropeptides-
dc.subject.meshPedigree-
dc.subject.meshPodocytes-
dc.subject.meshSequence Homology, Amino Acid-
dc.subject.meshrac GTP-Binding Proteins-
dc.titleArhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis.en_GB
dc.typeArticleen
dc.contributor.departmentDepartment of Pathology, Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.en_GB
dc.identifier.journalThe Journal of clinical investigationen_GB
dc.description.provinceLeinsteren

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