title: Inverted formin 2 regulates actin dynamics by antagonizing Rho/diaphanous-related formin signaling.
abstract: Mutations in inverted formin 2 INF2 are a common cause of familial FSGS. INF2 interacts with diaphanous-related formins (mDia) and antagonizes mDia-mediated actin polymerization in response to active Rho signaling, suggesting that dysregulation of these pathways may mediate the development of INF2-related FSGS. However, the precise mechanisms by which INF2 regulates actin-dependent podocyte behavior remain largely unknown. Here, we investigated the possible role of INF2 in both lamellipodia-associated actin dynamics and actin-dependent slit diaphragm (SD) protein trafficking by manipulating the expression of INF2 and the activity of Rho/mDia signaling in cultured podocytes. Activation of mDia in the absence of INF2 led to defective formation of lamellipodia and abnormal SD trafficking. Effects of mutations disrupting the INF2-mDia interaction suggested the specificity of the mDia-antagonizing effect of INF2 in maintaining the lamellipodium. Furthermore, we found that SD trafficking requires INF2 interaction with lipid raft components. In summary, INF2 regulates lamellipodial actin dynamics and the trafficking of slit diaphragm proteins by opposing Rho/mDia-mediated actin polymerization. Thus, in podocytes, INF2 appears to be an important modulator of actin-dependent behaviors that are under the control of Rho/mDia signaling.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.forename: Johannes
authors.initials: J
authors.lastname: Schlondorff
authors.forename: Henry N
authors.initials: HN
authors.lastname: Higgs
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
mesh_terms: D000199:Actins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002461:Cell Line, Transformed; D003600:Cytosol / Q000378:metabolism; D019281:Dimerization; D000080865:Formins; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D017354:Point Mutation; D020836:Protein Structure, Quaternary; D021381:Protein Transport / Q000502:physiology; D011554:Pseudopodia / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; D002352:Carrier Proteins; C491462:DIAPH2 protein, human; D000080865:Formins; C546959:INF2 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; C113267:nephrin; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein