The Formin INF2 Regulates Basolateral-to-Apical Transcytosis and Lumen Formation in Association with Cdc42 and MAL2

Madrid, Rodolfo; Aranda, Juan; Rodriguez-Fraticelli, Alejo; Ventimiglia, Leandro N.; Andrés-Delgado, Laura; Shehata, Mona; Fanayan, Susan; Shahheydari, Hamideh; Gómez, Sergio; Jiménez, Alberto; Martı́n-Belmonte, Fernando; Byrne, Jennifer A.; Alonso, Miguel A.

doi:10.1016/j.devcel.2010.04.001

Cited by 88 publications

(132 citation statements)

References 35 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…For example, the activity of INF2 or its immediate stimulators, such as cdc42 (43), could be regulated by Ca 2+ concentration. Such a possibility is represented by a second mathematical model, which is presented in Fig.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanical stimulation induces formin-dependent assembly of a perinuclear actin rim

Shao

Mogilner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

121

129

View full text Add to dashboard Cite

Cells constantly sense and respond to mechanical signals by reorganizing their actin cytoskeleton. Although a number of studies have explored the effects of mechanical stimuli on actin dynamics, the immediate response of actin after force application has not been studied. We designed a method to monitor the spatiotemporal reorganization of actin after cell stimulation by local force application. We found that force could induce transient actin accumulation in the perinuclear region within ∼2 min. This actin reorganization was triggered by an intracellular Ca 2+ burst induced by force application. Treatment with the calcium ionophore A23187 recapitulated the force-induced perinuclear actin remodeling. Blocking of actin polymerization abolished this process. Overexpression of Klarsicht, ANC-1, Syne Homology (KASH) domain to displace nesprins from the nuclear envelope did not abolish Ca 2+ -dependent perinuclear actin assembly. However, the endoplasmic reticulum-and nuclear membrane-associated inverted formin-2 (INF2), a potent actin polymerization activator (mutations of which are associated with several genetic diseases), was found to be important for perinuclear actin assembly. The perinuclear actin rim structure colocalized with INF2 on stimulation, and INF2 depletion resulted in attenuation of the rim formation. Our study suggests that cells can respond rapidly to external force by remodeling perinuclear actin in a unique Ca 2+ -and INF2-dependent manner.force | mechanotransduction | calcium | formin | perinuclear actin rim C ells can sense and adapt to their physical microenvironment through specific mechanosensing mechanisms. These properties are often mediated by the actin cytoskeleton, which can be modulated by a wide range of forces. Fluid shear stress, for example, induces actin stress fiber assembly and realignment along the direction of flow (1-4), whereas the cyclic stretch of an elastic substrate induces a reorientation of stress fibers under some angle to the direction of stretch (5-8). Applying mechanical force to cells by a microneedle results in focal adhesion growth and activation of formin-type actin nucleators (9, 10). Similarly, local application of force through fibronectin or collagen-coated beads trapped by optical or magnetic tweezers leads to the local reorganization of the actin cytoskeleton. This response is associated with reinforcement of bead attachment (11), recruitment of additional actin-associated proteins (12), and activation of a variety of signaling pathways (13)(14)(15)(16)(17). Most studies to date have explored the effects of force on actin structures directly associated with the sites of force application, such as focal adhesions and stress fibers. However, the immediate effect of force on the assembly of actin structures distal from the sites of force application has not been assessed. Such process is despite distal effects having potential implications in the transduction of local forces from the cell periphery to nuclear events (18).In this study, we used a local mecha...

show abstract

Section: Discussionmentioning

confidence: 99%

“…GFP-KASH (31) was a gift from Brian Burke (Institute of Medical Biology, Singapore). GFP-INF2 (isoform 1, C-terminal prenylated) was a gift from Miguel A. Alonso (Centro de Biologia Molecular Severo Ochoa, Madrid), and it was described previously (43). pDsRed2-ER vector, purchased from Clontech, was used to label ER.…”

Section: Methodsmentioning

confidence: 99%

Mechanical stimulation induces formin-dependent assembly of a perinuclear actin rim

Shao

Mogilner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

121

129

View full text Add to dashboard Cite

show abstract

“…In cells, does INF2 act to create filaments, to depolymerize filaments, or perhaps to create highly transient filaments, which it also depolymerizes? An approach to answering this question has been to use "polymerization" and "depolymerization" mutants to rescue effects of INF2 suppression in cells (23,24). The depolymerization mutant targeted the WH2 motif and has previously been shown biochemically to block depolymerization but not polymerization (20).…”

mentioning

confidence: 99%

“…The non-CAAX variant localizes in a cytoplasmic, actin-dependent meshwork pattern, and its suppression causes Golgi fragmentation (22). Suppression of INF2 in hepatocytic culture cells results in defects in transcytosis of apical proteins (23), whereas suppression in lymphocytic cells inhibits delivery of Lck to the plasma membrane (24). Physiologically, mutations in INF2 have been strongly linked to two human diseases: focal and segmental glomerulosclerosis (25)(26)(27)(28), a kidney disease, and Charcot-Marie Tooth disease, a peripheral neuropathy (29).…”

mentioning

confidence: 99%

Mutations to the Formin Homology 2 Domain of INF2 Protein Have Unexpected Effects on Actin Polymerization and Severing

Ramabhadran

Gurel

Higgs

2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: INF2 is a formin protein that accelerates both actin polymerization and depolymerization. Results: Mutations to highly conserved FH2 residues have surprising effects on INF2 biochemical activity. Conclusion: It is dangerous to assume that mutation of conserved FH2 domain residues will have equivalent effects on all formins. Significance: These studies provide mechanistic insight into the role of INF2's FH2 domain in polymerization and depolymerization.

show abstract

“…Among these were two transcription factors: hlh-8, encoding a helix-loop-helix (HLH) protein orthologous to TWIST, which regulates cellular movements in Drosophila and mammals (19,20); and crh-2, paralogous to SLBO, a C/EBPγ protein required for Drosophila border cell migration (7,8). Others genes were regulators of the actin cytoskeleton, such as toca-1 and inft-1/inverted formin (21,22). RNAi against inft-1 caused abnormal cell shapes, which paralleled the mutant phenotype of inft-1's mammalian ortholog INF2 (23).…”

mentioning

confidence: 99%

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Schwarz

Kato

Sternberg

2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

In both metazoan development and metastatic cancer, migrating cells must carry out a detailed, complex program of sensing cues, binding substrates, and moving their cytoskeletons. The linker cell in Caenorhabditis elegans males undergoes a stereotyped migration that guides gonad organogenesis, occurs with precise timing, and requires the nuclear hormone receptor NHR-67. To better understand how this occurs, we performed RNA-seq of individually staged and dissected linker cells, comparing transcriptomes from linker cells of third-stage (L3) larvae, fourth-stage (L4) larvae, and nhr-67-RNAi-treated L4 larvae. We observed expression of 8,000-10,000 genes in the linker cell, 22-25% of which were up-or downregulated 20-fold during development by NHR-67. Of genes that we tested by RNAi, 22% (45 of 204) were required for normal shape and migration, suggesting that many NHR-67-dependent, linker cell-enriched genes play roles in this migration. One unexpected class of genes up-regulated by NHR-67 was tandem pore potassium channels, which are required for normal linker-cell migration. We also found phenotypes for genes with human orthologs but no previously described migratory function. Our results provide an extensive catalog of genes that act in a migrating cell, identify unique molecular functions involved in nematode cell migration, and suggest similar functions in humans.major sperm protein | nematode development | transcriptional profiling | twin pore potassium channels | conserved uncharacterized proteins C ell migration is pervasive in animal development and is also an unwanted part of human cancer. Several different varieties of cell migration, ranging from social protozoa to the human immune system, have been extensively studied (1), but there remains a need for detailed analysis of the different components of migration in a simple cell type that can be exhaustively probed through anatomy, genetics, and genomics. We have undertaken to develop the linker cell (LC) of Caenorhabditis elegans as such a model. The LC is a single cell, attached to the front of a proliferating male gonad, which carries out a stereotypic, long-range migration to generate the shape of the mature gonad (Fig. 1A). During 25 h of the second to fourth larval stages (L2 through L4), the LC moves anteriorly along the ventral body wall, turns dorsally, proceeds posteriorly, switches sides once more to the ventral bodywall, continues posteriorward, reaches the cloaca, and eventually dies (2-4). Throughout this process, the proliferating and lengthening male gonad follows the LC's path to the cloaca. Stage-specific changes occur during the middle to late stages of migration (L3 and L4 larval stages): the LC changes shape from a spheroid to a pointed ellipsoid; it increases its speed of migration; and the netrin receptor gene unc-5 is down-regulated within the LC, which causes it to switch body walls ventrally ( Fig. 1A; ref. 3). These changes between the L3 and L4 stages require the orphan nuclear receptor NHR-67, whose orthologs TAILLESS and TLX...

show abstract

The Formin INF2 Regulates Basolateral-to-Apical Transcytosis and Lumen Formation in Association with Cdc42 and MAL2

Cited by 88 publications

References 35 publications

Mechanical stimulation induces formin-dependent assembly of a perinuclear actin rim

Mechanical stimulation induces formin-dependent assembly of a perinuclear actin rim

Mutations to the Formin Homology 2 Domain of INF2 Protein Have Unexpected Effects on Actin Polymerization and Severing

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Contact Info

Product

Resources

About