Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2)

Hua Sun, Johannes S. Schlondorff, Elizabeth J. Brown, Henry N. Higgs, Martin R. Pollak

Research output: Contribution to journalArticle

48 Citations (Scopus)

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. Weconfirmed 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.

Original languageEnglish (US)
Pages (from-to)2933-2938
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number7
DOIs
StatePublished - Feb 15 2011

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Serum Response Factor
Actins
Podocytes
Mutation
Polymerization
Transcriptional Activation
Protein Interaction Domains and Motifs
Focal Segmental Glomerulosclerosis
Kidney Diseases
Proteins
Yeasts
Phenotype
Genes

ASJC Scopus subject areas

  • General

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Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2). / Sun, Hua; Schlondorff, Johannes S.; Brown, Elizabeth J.; Higgs, Henry N.; Pollak, Martin R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 7, 15.02.2011, p. 2933-2938.

Research output: Contribution to journalArticle

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