Journal article
Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2)
Proceedings of the National Academy of Sciences - PNAS, Vol.108(7), pp.2933-2938
02/15/2011
DOI: 10.1073/pnas.1017010108
PMCID: PMC3041098
PMID: 21278336
Abstract
Inverted formin 2 (INF2) encodes a member of the diaphanous subfamily of formin proteins. Mutations in INF2 cause human kidney disease characterized by focal and segmental glomerulosclerosis. Disease-causing mutations occur only in the diaphanous inhibitory domain (DID), suggesting specific roles for this domain in the pathogenesis of disease. In a yeast two-hybrid screen, we identified the diaphanous autoregulatory domains (DADs) of the mammalian diaphanous-related formins (mDias) mDia1, mDia2, and mDia 3 as INF2_DID-interacting partners. The mDias are Rho family effectors that regulate actin dynamics. We confirmed in vitro INF2_DID/mDia_DAD binding by biochemical assays, confirmed the in vivo interaction of these protein domains by coimmunoprecipitation, and observed colocalization of INF2 and mDias in glomerular podocytes. We investigated the influence of this INF2_DID/mDia_DAD interaction on mDia mediated actin polymerization and on serum response factor (SRF) activation. We find that the interaction of INF2_DID with mDia_DAD inhibited mDia-mediated, Rho-activated actin polymerization, as well as SRF-responsive gene transcriptional changes. Similar assays using the disease-causing E184K and R218Q mutations in INF2_DID showed a decreased effect on SRF activation and gene transcription. The binding of INF2_DID to mDia_DAD may serve as a negative regulatory mechanism for mDias' function in actin-dependent cell processes. The effects of disease-causing INF2 mutations suggest an important role for this protein and its interaction with other formins in modulating glomerular podocyte phenotype and function.
Details
- Title: Subtitle
- Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2)
- Creators
- Hua Sun - Shanghai Children's Medical CenterJohannes S. Schlondorff - Harvard UniversityElizabeth J. Brown - Harvard UniversityHenry N. Higgs - Dartmouth CollegeMartin R. Pollak - Harvard University
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.108(7), pp.2933-2938
- Publisher
- Natl Acad Sciences
- DOI
- 10.1073/pnas.1017010108
- PMID
- 21278336
- PMCID
- PMC3041098
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Number of pages
- 6
- Grant note
- JDY08061 / Research Fund for Young Teachers at Shanghai University R01DK088826 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) DK080947; K12HD052896; GM069818; DK088826 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA K12HD052896 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) R01GM069818 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) 81000282/H0502 / Nature Science Foundation of China; National Natural Science Foundation of China (NSFC)
- Language
- English
- Date published
- 02/15/2011
- Academic Unit
- Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics
- Record Identifier
- 9984384321202771
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