Conversion of Mechanical Force into Biochemical Signaling

Han, Bing; Bai, Xiaohui; Lodyga, Monika; Xu, Jing; Yang, Burton B.; Keshavjee, Shaf; Post, Martin; Liu, Mingyao

doi:10.1074/jbc.m406880200

Cited by 144 publications

(139 citation statements)

References 43 publications

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“…Thus, we propose that mechano-chemical conversion may occur anywhere along the stress fiber length and not only at focal adhesions. This prediction is supported by recent experiments showing activation of the protein c-Src along stress fibers through binding to the mechanosensitive protein AFAP (Han et al, 2004). Activation of Src following application of a stress of 20 Pa by magnetic tweezers (Na et al, 2008) shows that the level of mechanical strain predicted by our model is sufficient to elicit such biological response.…”

Section: Stress Fibers: a Critical Link In The Mechanotransduction Chsupporting

confidence: 72%

“…We hypothesize that the relevant parameter for mechanical signal transmission through the cytoskeleton is not the force, which is virtually instantaneously transmitted within the cell, but rather the force-induced strain, whose development is delayed due to the viscoelasticity of stress fibers. In this new paradigm, the mechanical signal would induce protein activation not through stress but rather through strain, which has already been proposed as a possible mechanism for protein activation (Sawada and Sheetz, 2002;Han et al, 2004). Our results demonstrate that strain-mediated mechanical signal transmission through actin stress fibers allows a cell to integrate information derived from both the nature of the applied external force and the organization of the stress fibers.…”

Section: Introductionmentioning

confidence: 99%

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Model of cellular mechanotransduction via actin stress fibers

Gouget

Hwang

Barakat

2015

Biomech Model Mechanobiol

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Mechanical stresses due to blood flow regulate vascular endothelial cell structure and function and play a key role in arterial physiology and pathology. In particular, the development of atherosclerosis has been shown to correlate with regions of disturbed blood flow where endothelial cells are round and have a randomly organized cytoskeleton. Thus, deciphering the relation between the mechanical environment, cell structure and cell function is a key step towards understanding the early development of atherosclerosis. Recent experiments have demonstrated very rapid (∼100 msec) and long-distance (∼10 µm) cellular mechanotransduction in which prestressed actin stress fibers play a critical role. Here, we develop a model of mechanical signal transmission within a cell by describing strains in a network of prestressed viscoelastic stress fibers following the application of a force to the cell surface. We find force transmission dynamics that are consistent with experimental results. We also show that the extent of stress fiber alignment and the direction of the applied force relative to this alignment are key determinants of the efficiency of mechanical signal transmission. These results are consistent with the link observed experimentally between cytoskeletal organiza- tion, mechanical stress, and cellular responsiveness to stress. Based on these results, we suggest that mechanical strain of actin stress fibers under force constitutes a key link in the mechanotransduction chain.

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Section: Stress Fibers: a Critical Link In The Mechanotransduction Chsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Model of cellular mechanotransduction via actin stress fibers

Gouget

Hwang

Barakat

2015

Biomech Model Mechanobiol

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“…7,8 Briefly, cells were lysed with modified radioimmune precipitation assay buffer (50 mmol/L Tris-HCl, pH 7.5; 150 mmol/L NaCl; 2 mmol/L EGTA; 2 mmol/L EDTA; and 1% Triton X-100) containing 10 g/ml each aprotinin, leupeptin, pepstatin, 1 mmol/L phenylmethylsulfonyl fluoride, 1 mmol/L Na 3 VO 4 , and 10 mmol/L NaF. Protein concentration was measured by a modified Bradford assay (Bio-Rad, Hercules, CA).…”

Section: Protein Studiesmentioning

confidence: 99%

“…[7][8][9] The human xb130 gene encodes 818 amino acids and has an apparent molecular size of approximately 130 kDa. As an adaptor protein, the overall structure of XB130 shares similarity with AFAP, so it is also known as actin filament associated protein 1-like 2 (AFAP1L2).…”

mentioning

confidence: 99%

XB130, a Novel Adaptor Protein, Promotes Thyroid Tumor Growth

Shiozaki

Lodyga

Bai

et al. 2011

The American Journal of Pathology

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Adaptor proteins with multimodular structures can participate in the regulation of various cellular functions. We have cloned a novel adaptor protein, XB130, which binds the p85␣ subunit of phosphatidyl inositol 3-kinase and subsequently mediates signaling through RET/ PTC in TPC-1 thyroid cancer cells. In the present study, we sought to determine the role of XB130 in the tumorigenesis in vivo and in related molecular mechanisms. In WRO thyroid cancer cells, knockdown of XB130 using small interfering RNA inhibited G 1 -S phase progression, induced spontaneous apoptosis, and enhanced intrinsic and extrinsic apoptotic stimulus-induced cell death. Growth of tumors in nude mice formed from XB130 shRNA stably transfected WRO cells were significantly reduced, with decreased cell proliferation and increased apoptosis. Microarray analysis identified 246 genes significantly changed in XB130 shRNA transfected cells. Among them, 57 genes are related to cell proliferation or survival, including many transcription regulators. Ingenuity Pathway Analysis showed that the topranked disease related to XB130 is cancer, and the top molecular and cellular functions are cellular growth and proliferation and cell cycle. A human thyroid tissue microarray study identified expression of XB130 in normal thyroid tissue as well as in human thyroid carcinomas. These observations suggest that the expression of XB130 in these cancer cells may affect cell proliferation and survival by controlling the expression of multiple genes, especially transcription regulators.

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“…During our recent studies aimed at the characterization of the actin filament-associated protein (AFAP; Flynn et al, 1993;Lodyga et al, 2002;Han et al, 2004), we cloned a novel 130 kDa protein, referred to as XB130 (Xu et al, 2007). The human xb130 gene is localized on chromosome 10q25.3, and encodes an 818 amino-acid protein that shares 35% similarity with AFAP.…”

Section: Introductionmentioning

confidence: 99%

XB130, a tissue-specific adaptor protein that couples the RET/PTC oncogenic kinase to PI 3-kinase pathway

et al. 2008

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XB130 is a recently cloned 130 kDa-adaptor protein and Src kinase substrate, structurally similar to actin-filamentassociated protein. Here we show that XB130 is predominantly expressed in the thyroid. Given that XB130 is a thyroid-specific tyrosine kinase substrate, we asked whether it is targeted by RET/PTC, a genetically rearranged, constitutively active, thyroid-specific tyrosine kinase that plays a pathogenic role in papillary thyroid cancer. RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85a subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85a. Importantly, downregulation of XB130 in TPC1 papillary thyroid cancer cells, harboring the RET/PTC1 kinase, strongly reduced Akt activity without altering ERK1/2 phosphorylation, and concomitantly inhibited cell-cycle progression and survival in suspension. In conclusion, XB130 is a novel substrate of the RET/PTC kinase that links RET/PTC signaling to PI 3-kinase activation, and thereby plays an important role in sustaining proliferation and survival of thyroid tumor cells.

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Conversion of Mechanical Force into Biochemical Signaling

Cited by 144 publications

References 43 publications

Model of cellular mechanotransduction via actin stress fibers

Model of cellular mechanotransduction via actin stress fibers

XB130, a Novel Adaptor Protein, Promotes Thyroid Tumor Growth

XB130, a tissue-specific adaptor protein that couples the RET/PTC oncogenic kinase to PI 3-kinase pathway

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