Recapitulation of molecular regulators of nuclear motion during cell migration

Sneider, Alexandra; Hah, Jungwon; Wirtz, Denis; Kim, Dong-Hwee

doi:10.1080/19336918.2018.1506654

Cited by 18 publications

(19 citation statements)

References 138 publications

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“…A force-induced nuclear lamina triggers the deformation of intranuclear structures (e.g., chromatin and nuclear bodies) and initiates changes in gene regulation [6,7]. As the center of the mechanical response of a cell, the nucleus properly adapts to mechanical stimuli by altering its position and characteristics during the regulation of cellular functions [8,9].…”

Section: Introductionmentioning

confidence: 99%

Deciphering Nuclear Mechanobiology in Laminopathy

Hah

Kim

2019

Cells

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Extracellular mechanical stimuli are translated into biochemical signals inside the cell via mechanotransduction. The nucleus plays a critical role in mechanoregulation, which encompasses mechanosensing and mechanotransduction. The nuclear lamina underlying the inner nuclear membrane not only maintains the structural integrity, but also connects the cytoskeleton to the nuclear envelope. Lamin mutations, therefore, dysregulate the nuclear response, resulting in abnormal mechanoregulations, and ultimately, disease progression. Impaired mechanoregulations even induce malfunction in nuclear positioning, cell migration, mechanosensation, as well as differentiation. To know how to overcome laminopathies, we need to understand the mechanisms of laminopathies in a mechanobiological way. Recently, emerging studies have demonstrated the varying defects from lamin mutation in cellular homeostasis within mechanical surroundings. Therefore, this review summarizes recent findings highlighting the role of lamins, the architecture of nuclear lamina, and their disease relevance in the context of nuclear mechanobiology. We will also provide an overview of the differentiation of cellular mechanics in laminopathy.

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Section: Introductionmentioning

confidence: 99%

Deciphering Nuclear Mechanobiology in Laminopathy

Hah

Kim

2019

Cells

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“…Refilin A (RFLNA) is a member of the refilin family (RFLNA and RFLNB), which are filamin-binding short-lived actin regulators coordinating nuclear movements in complex processes such as cell migration and differentiation [45], but also the dynamics of lamellipodium protrusions [46]. Since both refilin proteins are unstable proteins, the consequence of a cytosolic reduction of RFLNA by its mistargeting to peroxisomes is hard to predict.…”

Section: Resultsmentioning

confidence: 99%

Rare Human Missense Variants can affect the Function of Disease-Relevant Proteins by Loss and Gain of Peroxisomal Targeting Motifs

Chong

Kunze

Hochreiter

et al. 2019

IJMS

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Single nucleotide variants (SNVs) resulting in amino acid substitutions (i.e., missense variants) can affect protein localization by changing or creating new targeting signals. Here, we studied the potential of naturally occurring SNVs from the Genome Aggregation Database (gnomAD) to result in the loss of an existing peroxisomal targeting signal 1 (PTS1) or gain of a novel PTS1 leading to mistargeting of cytosolic proteins to peroxisomes. Filtering down from 32,985 SNVs resulting in missense mutations within the C-terminal tripeptide of 23,064 human proteins, based on gene annotation data and computational prediction, we selected six SNVs for experimental testing of loss of function (LoF) of the PTS1 motif and five SNVs in cytosolic proteins for gain in PTS1-mediated peroxisome import (GoF). Experimental verification by immunofluorescence microscopy for subcellular localization and FRET affinity measurements for interaction with the receptor PEX5 demonstrated that five of the six predicted LoF SNVs resulted in loss of the PTS1 motif while three of five predicted GoF SNVs resulted in de novo PTS1 generation. Overall, we showed that a complementary approach incorporating bioinformatics methods and experimental testing was successful in identifying SNVs capable of altering peroxisome protein import, which may have implications in human disease.

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“…Nuclear membrane is tightly connected to integrin‐based focal adhesion through cytoskeletal fibers that can transmit external force or cytoskeletal tension to the nuclear membrane, causing structural deformation of the nucleus. [ 5 ] Applied force not only changes nuclear shape, but also determines the conformation of many proteins located in nuclear membrane associated with various biochemical signals. [ 6 ] Since transcriptional regulatory mechanisms, such as histone modification and transcription factor activity, are controlled by force‐mediated nuclear deformation, signal pathways for nuclear mechanosensation have been focused to interpret cellular adaptation mechanism including stem cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

Mechanical Properties of Materials for Stem Cell Differentiation

et al. 2020

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Traditionally, understanding differentiation pathway has been achieved by studying biochemical signal pathways controlled by various growth factors and cytokines. However, since various physical factors including tissue stiffness and topology can also determine the differentiation pathway of stem cells, mechanobiological pathway for controlling differentiation has been emphasized. Moreover, newly identified mechanobiological pathways have encouraged efforts to interpret stem cell differentiation in terms of cell-material interaction and provided clues to accurately design microenvironment of stem cells to control the direction of differentiation. Cells continuously recognize topographical and mechanical properties of the surrounding microenvironment and modulate their functional phenotypes through appropriate physiological responses to maintain homeostasis. Cell-cell and cell-extracellular matrix (ECM) interactions determine physical connections between the outside and the inside of individual cells to regulate various cellular functions, including adhesion, migration, proliferation, and cell differentiation. [3] Integrin, a transmembrane protein, is actively involved in outside-in and inside-out signaling mediated by polymerization and contraction of the cytoskeleton known to control cellular mechanotransduction pathways. [4] Therefore, a changed physical microenvironment can be detected by integrin-ECM interaction which has been traditionally considered as a primary target for controlling cell behavior through the material properties. Recent studies have shown that nuclear mechanosensation is a key process in response to physical stimuli. Nuclear membrane is tightly connected to integrin-based focal adhesion through cytoskeletal fibers that can transmit external force or cytoskeletal tension to the nuclear membrane, causing structural deformation of the nucleus. [5] Applied force not only changes nuclear shape, but also determines the conformation of many proteins located in nuclear membrane associated with various biochemical signals. [6] Since transcriptional regulatory mechanisms, such as histone modification and transcription factor activity, are controlled by force-mediated nuclear deformation, signal pathways for nuclear mechanosensation have been focused to interpret cellular adaptation mechanism including stem cell differentiation. [7] Various methods have been used to determine cell functions by changing cell adhesion through the corresponding changes in external substrates using micropatterned cell confinement, micro-/nanosized topographic substrates, and substrate stiffness. Micropatterning of ECM proteins is a well-established method to Recent findings about cell fate change induced by physical stimuli have expedited the discovery of underlying regulatory mechanisms that determine stem cell differentiation. Progress with regards to micro-/nanofabrication technology have led to the development of advanced materials that can mimic biophysical features of in vivo related circumstances of the human body...

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Recapitulation of molecular regulators of nuclear motion during cell migration

Cited by 18 publications

References 138 publications

Deciphering Nuclear Mechanobiology in Laminopathy

Deciphering Nuclear Mechanobiology in Laminopathy

Rare Human Missense Variants can affect the Function of Disease-Relevant Proteins by Loss and Gain of Peroxisomal Targeting Motifs

Mechanical Properties of Materials for Stem Cell Differentiation

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