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FHOD1 is needed for directed forces and adhesion maturation during cell spreading and migration.

ABSTRACT: Matrix adhesions provide critical signals for cell growth or differentiation. They form through a number of distinct steps that follow integrin binding to matrix ligands. In an early step, integrins form clusters that support actin polymerization by an unknown mechanism. This raises the question of how actin polymerization occurs at the integrin clusters. We report here that a major formin in mouse fibroblasts, FHOD1, is recruited to integrin clusters, resulting in actin assembly. Using cell-spreading assays on lipid bilayers, solid substrates, and high-resolution force-sensing pillar arrays, we find that knockdown of FHOD1 impairs spreading, coordinated application of adhesive force, and adhesion maturation. Finally, we show that targeting of FHOD1 to the integrin sites depends on the direct interaction with Src family kinases and is upstream of the activation by Rho kinase. Thus, our findings provide insights into the mechanisms of cell migration with implications for development and disease.

SUBMITTER: Iskratsch T

PROVIDER: S-EPMC3890431 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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FHOD1 is needed for directed forces and adhesion maturation during cell spreading and migration.

Iskratsch Thomas T Yu Cheng-Han CH Mathur Anurag A Liu Shuaimin S Stévenin Virginie V Dwyer Joseph J Hone James J Ehler Elisabeth E Sheetz Michael M

Developmental cell 20131201 5

Matrix adhesions provide critical signals for cell growth or differentiation. They form through a number of distinct steps that follow integrin binding to matrix ligands. In an early step, integrins form clusters that support actin polymerization by an unknown mechanism. This raises the question of how actin polymerization occurs at the integrin clusters. We report here that a major formin in mouse fibroblasts, FHOD1, is recruited to integrin clusters, resulting in actin assembly. Using cell-spr ...[more]

PMID: 24331927

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Project description:Actin-based cell motility and force generation are central to immune response, tissue development, and cancer metastasis, and understanding actin cytoskeleton regulation is a major goal of cell biologists. Cell spreading is a commonly used model system for motility experiments -- spreading fibroblasts exhibit stereotypic, spatially-isotropic edge dynamics during a reproducible sequence of functional phases: 1) During early spreading, cells form initial contacts with the surface. 2) The middle spreading phase exhibits rapidly increasing attachment area. 3) Late spreading is characterized by periodic contractions and stable adhesions formation. While differences in cytoskeletal regulation between phases are known, a global analysis of the spatial and temporal coordination of motility and force generation is missing. Implementing improved algorithms for analyzing edge dynamics over the entire cell periphery, we observed that a single domain of homogeneous cytoskeletal dynamics dominated each of the three phases of spreading. These domains exhibited a unique combination of biophysical and biochemical parameters -- a motility module. Biophysical characterization of the motility modules revealed that the early phase was dominated by periodic, rapid membrane blebbing; the middle phase exhibited continuous protrusion with very low traction force generation; and the late phase was characterized by global periodic contractions and high force generation. Biochemically, each motility module exhibited a different distribution of the actin-related protein VASP, while inhibition of actin polymerization revealed different dependencies on barbed-end polymerization. In addition, our whole-cell analysis revealed that many cells exhibited heterogeneous combinations of motility modules in neighboring regions of the cell edge. Together, these observations support a model of motility in which regions of the cell edge exhibit one of a limited number of motility modules that, together, determine the overall motility function. Our data and algorithms are publicly available to encourage further exploration.

Dataset Information

FHOD1 is needed for directed forces and adhesion maturation during cell spreading and migration.

Publications

FHOD1 is needed for directed forces and adhesion maturation during cell spreading and migration.

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