The multiplicity of human formins: Expression patterns in cells and tissues

Krainer, Elisabeth C.; Ouderkirk, Jessica L.; Miller, Eugene H.; Miller, Matthew; Mersich, Akos T.; Blystone, Scott D.

doi:10.1002/cm.21113

Cited by 44 publications

(60 citation statements)

References 41 publications

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“…Arp2/3 forms the branched network in lamellipodia and is thought to be linked to nascent FAs through interaction with FAK (19)(20)(21) or vinculin (22). The formin family of actin nucleators, which generates linear actin bundles (23), is more diverse, although formins share a common actin assembly core domain (24), (25). Recent work has begun to ascribe the generation of particular actin structures to some of the 15 formins in mammalian cells, particularly members of the diaphanous family and FHOD1 (26)(27)(28)(29).…”

Section: Significancementioning

confidence: 99%

RETRACTED: Inverted formin 2 in focal adhesions promotes dorsal stress fiber and fibrillar adhesion formation to drive extracellular matrix assembly

Skau

Plotnikov

Doyle

et al. 2015

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

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Actin filaments and integrin-based focal adhesions (FAs) form integrated systems that mediate dynamic cell interactions with their environment or other cells during migration, the immune response, and tissue morphogenesis. How adhesion-associated actin structures obtain their functional specificity is unclear. Here we show that the formin-family actin nucleator, inverted formin 2 (INF2), localizes specifically to FAs and dorsal stress fibers (SFs) in fibroblasts. High-resolution fluorescence microscopy and manipulation of INF2 levels in cells indicate that INF2 plays a critical role at the SF–FA junction by promoting actin polymerization via free barbed end generation and centripetal elongation of an FA-associated actin bundle to form dorsal SF. INF2 assembles into FAs during maturation rather than during their initial generation, and once there, acts to promote rapid FA elongation and maturation into tensin-containing fibrillar FAs in the cell center. We show that INF2 is required for fibroblasts to organize fibronectin into matrix fibers and ultimately 3D matrices. Collectively our results indicate an important role for the formin INF2 in specifying the function of fibrillar FAs through its ability to generate dorsal SFs. Thus, dorsal SFs and fibrillar FAs form a specific class of integrated adhesion-associated actin structure in fibroblasts that mediates generation and remodeling of ECM.

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Section: Significancementioning

confidence: 99%

RETRACTED: Inverted formin 2 in focal adhesions promotes dorsal stress fiber and fibrillar adhesion formation to drive extracellular matrix assembly

Skau

Plotnikov

Doyle

et al. 2015

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

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“…Complete blood counts were surprisingly normal, indicating that FMNL1 is unlikely to serve a critical role in hematopoiesis. In addition to FMNL1, we have previously reported that other formins, such as Dia1 and FHOD1, are expressed in macrophages (Krainer et al, 2013), yet we observed no compensatory changes in the expression of other formins when FMNL1 was depleted from macrophages here. Strikingly, the tissue distribution of residential macrophages from knockout mice was significantly reduced compared to in WT, most notably in the liver.…”

Section: Discussioncontrasting

confidence: 47%

Non-canonical activity of the podosomal formin FMNL1γ supports immune cell migration

Miller

Blystone

2017

Journal of Cell Science

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Having previously located the formin FMNL1 in macrophage podosomes, we developed an in vivo model to assess the role of FMNL1 in the migration activities of primary macrophages. Deletion of FMNL1 in mice was genetically lethal; however, targeted deletion in macrophages was achieved by employing macrophage-specific Cre. Unchallenged FMNL1-deficient mice exhibited an unexpected reduction in tissue-resident macrophages despite normal blood monocyte numbers. Upon immune stimulus, the absence of FMNL1 resulted in reduced macrophage recruitment in vivo, decreased migration in two-dimensional in vitro culture and a decrease in the number of macrophages exhibiting podosomes. Of the three described isoforms of FMNL1 -α, β and γ -only FMNL1γ rescued macrophage migration when expressed exogenously in depleted macrophages. Surprisingly, mutation of residues in the FH2 domain of FMNL1γ that disrupt barbed-end actin binding did not limit rescue of macrophage migration and podosome numbers. These observations suggest that FMNL1 contributes to macrophage migration activity by stabilizing the lifespan of podosomes without interaction of fast-growing actin termini.

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“…2E); IMM-02 showed an equivocal effect. The difference in induction of stabilization between treated and untreated NIH 3T3 and SW480 cells is unclear; it may reflect fundamental differences in dynamic instability of transformed and nontransformed cells (31,33), or alternatively, the nature of the affected target formin expressed in these two different cell types (34).…”

Section: Resultsmentioning

confidence: 99%

Small-Molecule Intramimics of Formin Autoinhibition: A New Strategy to Target the Cytoskeletal Remodeling Machinery in Cancer Cells

et al. 2013

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Although the cancer cell cytoskeleton is a clinically validated target, few new strategies have emerged for selectively targeting cell division by modulating the cytoskeletal structure, particularly ways that could avoid the cardiotoxic and neurotoxic effects of current agents such as taxanes. We address this gap by describing a novel class of small-molecule agonists of the mammalian Diaphanous (mDia)-related formins, which act downstream of Rho GTPases to assemble actin filaments, and their organization with microfilaments to establish and maintain cell polarity during migration and asymmetric division. GTP-bound Rho activates mDia family members by disrupting the interaction between the DID and DAD autoregulatory domains, which releases the FH2 domain to modulate actin and microtubule dynamics. In screening for DID-DAD disruptors that activate mDia, we identified two molecules called intramimics (IMM-01 and -02) that were sufficient to trigger actin assembly and microtubule stabilization, serum response factor-mediated gene expression, cell-cycle arrest, and apoptosis. In vivo analysis of IMM-01 and -02 established their ability to slow tumor growth in a mouse xenograft model of colon cancer. Taken together, our work establishes the use of intramimics and mDia-related formins as a new general strategy for therapeutic targeting of the cytoskeletal remodeling machinery of cancer cells. Cancer Res; 73(22); 6793-803. Ó2013 AACR.

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The multiplicity of human formins: Expression patterns in cells and tissues

Cited by 44 publications

References 41 publications

RETRACTED: Inverted formin 2 in focal adhesions promotes dorsal stress fiber and fibrillar adhesion formation to drive extracellular matrix assembly

RETRACTED: Inverted formin 2 in focal adhesions promotes dorsal stress fiber and fibrillar adhesion formation to drive extracellular matrix assembly

Non-canonical activity of the podosomal formin FMNL1γ supports immune cell migration

Small-Molecule Intramimics of Formin Autoinhibition: A New Strategy to Target the Cytoskeletal Remodeling Machinery in Cancer Cells

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