GEF-H1 controls focal adhesion signaling that regulates mesenchymal stem cell lineage commitment

Huang, I-Husan; Hsiao, Cheng-Te; Wu, Jui-Chung; Shen, Rong-Fong; Liu, Ching-Yi; Wang, Yang-Kao; Chen, Yu‐Chen; Huang, Chi-Ming; Álamo, Juan C. del; Chang, Zee-Fen; Tang, Min; Khoo, Kay‐Hooi; Kuo, Jean Cheng

doi:10.1242/dev.117994

Cited by 6 publications

(7 citation statements)

References 50 publications

(87 reference statements)

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“…Stress fibre formation and focal adhesion formation also depends on GEF-H1, which stimulates RhoA along the basal membrane and drives focal adhesion formation in various cell types. GEF-H1 is recruited to tight junctions by cingulin, which then leads to inhibition of the GEF, similar to the inhibition of this GEF by binding to microtubules (Table 1) [160][161][162][163][164][165] . While a role for ZO-1 in suppressing focal adhesion formation has so far only been demonstrated in endothelial cells, disruption of tight junction formation and stress fibre formation by depletion of p114RhoGEF, a GEF that supports junction formation, occurs in endothelial and epithelial cells 114 .…”

Section: Crosstalk With Other Adhesion Complexesmentioning

confidence: 99%

Tight junctions: from simple barriers to multifunctional molecular gates

Zihni

Mills

Matter

et al. 2016

Nat Rev Mol Cell Biol

1,150

925

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Main body of text: 5983 words 2Epithelia and endothelia separate different tissue compartments and protect multicellular organisms form the outside world. This requires the formation of tight junctions, selective gates that control paracellular diffusion of ions and solutes. Tight junctions also form the border between the apical and basolateral plasma membrane domains and are linked to the machinery that controls apicobasal polarization. Additionally, signalling networks that guide diverse cell behaviours and functions are connected to tight junctions, transmitting information to and from the cytoskeleton, nucleus and different cell adhesion complexes. Here, we discuss recent advances in our understanding of the molecular architecture and cellular functions of tight junctions.Microscopists in the 19 th century described the paracellular space between neighbouring cells within an epithelial sheet to be sealed by a "terminal bar", a structure later resolved by electron microscopy into a composite of distinct cell-cell junctions that is now called the epithelial junctional complex and is formed by tight junctions, adherens junctions and desmosomes 1,2 . As the former two junctions are more tightly associated and often reside at the apical end of the lateral membrane, they are often referred to as the apical junctional complex (however, in endothelia, tight junctions and adherens junctions can be intercalated) (Fig. 1). Tight junctions are essential for barrier formation, and their primary physiological role is to function as paracellular gates that restrict diffusion on the basis of size and charge. Selective paracellular diffusion is an essential process for the maintenance of homoeostasis in organs and tissues. Tight junctions have long been the most enigmatic of all adhesion complexes and eluded a detailed molecular and functional analysis due to their complex architecture. Recent years have witnessed the identification of a large array of components associated with tight junctions implicating these junctions in an unexpected range of different functions, thereby challenging the traditional model, in which tight junctions are considered a simple diffusion barrier formed by a rigid molecular complex. In line with these various functions, mutations in genes encoding tight junction proteins have been linked to a range of inherited human diseases. Additionally, tight junction components are known to be targeted by a number of pathogenic bacteria and viruses, which hijack tight junction proteins to enter and infect cells, or target junctional signalling mechanisms to cross tissue barriers. Although tight junctions are a vertebrate junction, many of their components and functions are evolutionarily conserved (Box 1).The main purpose of this review is to examine the recent advances in the unravelling of the molecular architecture of tight junctions and understanding their functions. We will discuss recent exciting insights into how tight junctions function as signalling platforms that guide cell behaviour and differen...

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Section: Crosstalk With Other Adhesion Complexesmentioning

confidence: 99%

Tight junctions: from simple barriers to multifunctional molecular gates

Zihni

Mills

Matter

et al. 2016

Nat Rev Mol Cell Biol

1,150

925

View full text Add to dashboard Cite

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“…Application of MSCs to cell therapy or tissue engineering requires an understanding of how to maintain and differentiate MSCs both in vitro and in vivo [27,28]. Moreover, ECM elasticity, ECM composition, integrins and their associated adhesion complex components are now widely appreciated to play roles in MSC growth, differentiation and homing [14,[29][30][31]. FN is a component of the ECM that has been shown to regulate stem cell biology in a variety of systems including MSC cell fate decisions [32][33][34][35].…”

Section: Clinical Relevancementioning

confidence: 99%

Proteomic analysis of integrin‐associated complexes from mesenchymal stem cells

Ajeian

Horton

Astudillo

et al. 2015

Proteomics Clinical Apps

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PurposeMultipotent mesenchymal stem cells (MSCs) have the capability to differentiate down adipocyte, osteocyte and chondrocyte lineages and as such offer a range of potential therapeutic applications. The composition and stiffness of the extracellular matrix (ECM) environment that surrounds cells dictates their transcriptional programme, thereby affecting stem cell lineage decision‐making. Cells sense force via linkages between themselves and their microenvironment, and this is transmitted by integrin receptors and associated adhesion signalling complexes. To identify regulators of MSC force sensing, we sought to catalogue MSC integrin‐associated adhesion complex composition.Experimental designAdhesion complexes formed by MSCs plated on the ECM ligand fibronectin were isolated and characterised by MS. Identified proteins were interrogated by comparison to a literature‐based reference set of cell adhesion‐related components and using ontological and protein–protein interaction network analyses.ResultsAdhesion complex‐specific proteins in MSCs were identified that comprised predominantly cell adhesion‐related adaptors and actin cytoskeleton regulators. Furthermore, LIM domain‐containing proteins in MSC adhesion complexes were highlighted, which may act as force‐sensing components.Conclusion and clinical relevanceThese data provide a valuable resource of information regarding the molecular connections that link integrins and adhesion signalling in MSCs, and as such may present novel opportunities for therapeutic intervention.

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“…Rho guanine nucleotide exchange factor (5) is a protein which regulates the activity of Rho GTP enzyme through regulating the exchange of GDP/GTP (6). GEF-H1 has a wide range of biological functions, such as regulating vesicle transport and cell movement (6,7), stabling cytoskeleton (8), affecting the cell barrier function (9)(10)(11)(12), promoting cell cycle progression and inhibiting cell apoptosis and other biological functions (5,10,(12)(13)(14)(15). GEF-H1 has been reported to have abnormal activation in many types of cancers, such as breast, prostate and myeloid cell cancer (10,(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

miR-194 is a negative regulator of GEF-H1 pathway in melanoma

et al. 2016

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The incidence and associated mortality of melanoma continues to increase worldwide. At present, there is no curative therapy for advanced stage of melanoma. It is necessary to find new indicators of prognosis and therapeutic targets. Increasing evidence shows that miRNA can provide potential candidate biomarkers for melanoma and therapeutic targets. GEF-H1, a regulator of RhoA, as oncogenic driver in melanoma, promotes the growth and invasion of melanoma. miR-194 is a tumor-suppressor gene in multiple tumors, such as bladder and non-small cell lung cancer, and clear cell renal cell carcinoma. In the present study, we demonstrated that GEF-H1 serves as target of miR-194. Overexpression of miR-194 downregulates the GEF-H1/RhoA pathway, inhibits melanoma cancer cell proliferation and metastasis. Furthermore, miR-194 expression is negatively associated with tumor-node-metastasis (TNM) stages. Briefly, our findings provided new theoretical basis for melanoma treatment.

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GEF-H1 controls focal adhesion signaling that regulates mesenchymal stem cell lineage commitment

Cited by 6 publications

References 50 publications

Tight junctions: from simple barriers to multifunctional molecular gates

Tight junctions: from simple barriers to multifunctional molecular gates

Proteomic analysis of integrin‐associated complexes from mesenchymal stem cells

miR-194 is a negative regulator of GEF-H1 pathway in melanoma

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