CLIC4 mediates and is required for Ca2+-induced keratinocyte differentiation

Suh, Kwang S.; Mutoh, Michihiro; Mutoh, Tomoko; Li, Luowei; Ryscavage, Andrew; Crutchley, John; Dumont, Rebecca A.; Cheng, Christina; Yuspa, Stuart H.

doi:10.1242/jcs.002741

Cited by 54 publications

(61 citation statements)

References 57 publications

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“…Nuclear translocation of CLIC4 is essential for its proapoptotic, prodifferentiation, and cell growth arrest functions (10,14,30). In this study we have established that nuclear translocation of CLIC4 is regulated by S-nitrosylation of the protein.…”

Section: Discussionmentioning

confidence: 73%

“…CLIC4 has emerged as a crucial player in many physiological processes, including tubular morphogenesis during angiogenesis (5-7), transdifferentiation of mammary fibroblasts to myofibroblasts in response to TGF-␤ (8), and adipocyte differentiation (9). CLIC4 has been established as a significant effector of mouse and human keratinocyte differentiation, associated with G 1 cell cycle arrest and expression of differentiation markers (10).…”

Section: Nuclear Translocation Of Chloride Intracellular Channel Protmentioning

confidence: 99%

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S-Nitrosylation Regulates Nuclear Translocation of Chloride Intracellular Channel Protein CLIC4

Malik

Shukla

Amin

et al. 2010

Journal of Biological Chemistry

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Nuclear translocation of chloride intracellular channel protein CLIC4 is essential for its role in Ca2؉ -induced differentiation, stress-induced apoptosis, and modulating TGF-␤ signaling in mouse epidermal keratinocytes. However, post-translational modifications on CLIC4 that govern nuclear translocation and thus these activities remain to be elucidated. The structure of CLIC4 is dependent on the redox environment, in vitro, and translocation may depend on reactive oxygen and nitrogen species in the cell. Here we show that NO directly induces nuclear translocation of CLIC4 that is independent of the NO-cGMP pathway. Indeed, CLIC4 is directly modified by NO through S-nitrosylation of a cysteine residue, as measured by the biotin switch assay. NO enhances association of CLIC4 with the nuclear import proteins importin ␣ and Ran. This is likely a result of the conformational change induced by S-nitrosylated CLIC4 that leads to unfolding of the protein, as exhibited by CD spectra analysis and trypsinolysis of the modified protein. Cysteine mutants of CLIC4 exhibit altered nitrosylation, nuclear residence, and stability, compared with the wild type protein likely as a consequence of altered tertiary structure. Moreover, tumor necrosis factor ␣-induced nuclear translocation of CLIC4 is dependent on nitric-oxide synthase activity. Inhibition of nitric-oxide synthase activity inhibits tumor necrosis factor ␣-induced nitrosylation and association with importin ␣ and Ran and ablates CLIC4 nuclear translocation. These results suggest that S-nitrosylation governs CLIC4 structure, its association with protein partners, and thus its intracellular distribution.CLIC4 (chloride intracellular channel protein 4) belongs to a family of differentially expressed chloride channel proteins that are largely conserved from Caenorhabditis elegans to humans.Various members have been implicated in cell signaling cascades, ranging from stimulation of chloride channel activity by CLIC3 following association with extracellular signal-regulated kinase (ERK) 7 (1) to CLIC5A that is implicated in bone resorption and HCl transport in osteoclasts, in response to phosphorylation by c-Src (2). However, a number of functions of CLIC proteins are independent of channel activity (3, 4).The best characterized of the CLIC family members is CLIC4, identified in our laboratory as a p53 and TNF␣ 2 response gene that is up-regulated during keratinocyte differentiation. CLIC4 has emerged as a crucial player in many physiological processes, including tubular morphogenesis during angiogenesis (5-7), transdifferentiation of mammary fibroblasts to myofibroblasts in response to TGF-␤ (8), and adipocyte differentiation (9). CLIC4 has been established as a significant effector of mouse and human keratinocyte differentiation, associated with G 1 cell cycle arrest and expression of differentiation markers (10).An intriguing aspect of CLIC4 biology is its role as an effector of apoptosis, including p53-and c-Myc-induced apoptosis, as well as in response to cytotoxic and ...

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Section: Discussionmentioning

confidence: 73%

Section: Nuclear Translocation Of Chloride Intracellular Channel Protmentioning

confidence: 99%

S-Nitrosylation Regulates Nuclear Translocation of Chloride Intracellular Channel Protein CLIC4

Malik

Shukla

Amin

et al. 2010

Journal of Biological Chemistry

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“…CLIC4 is ubiquitously expressed and detected in the cytosol as a diffusible protein, but it can also localize to intracellular vesicles, organelles and actin-based structures (Berryman and Goldenring, 2003;Chuang et al, 1999;Chuang et al, 2010) and even to the nucleus (Shukla et al, 2009;Suh et al, 2007). Growing evidence points to a role for CLIC4 in such diverse processes as angiogenesis, differentiation, migration and wound healing.…”

Section: Introductionmentioning

confidence: 99%

CLIC4 regulates cell adhesion and β1 integrin trafficking

Argenzio

Margadant

Leyton-Puig

et al. 2014

Journal of Cell Science

100

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BSTRACTChloride intracellular channel protein 4 (CLIC4) exists in both soluble and membrane-associated forms, and is implicated in diverse cellular processes, ranging from ion channel formation to intracellular membrane remodeling. CLIC4 is rapidly recruited to the plasma membrane by lysophosphatidic acid (LPA) and serum, suggesting a possible role for CLIC4 in exocytic-endocytic trafficking. However, the function and subcellular target(s) of CLIC4 remain elusive. Here, we show that in HeLa and MDA-MB-231 cells, CLIC4 knockdown decreases cell-matrix adhesion, cell spreading and integrin signaling, whereas it increases cell motility. LPA stimulates the recruitment of CLIC4 to b1 integrin at the plasma membrane and in Rab35-positive endosomes. CLIC4 is required for both the internalization and the serum-or LPA-induced recycling of b1 integrin, but not for EGF receptor trafficking. Furthermore, we show that CLIC4 suppresses Rab35 activity and antagonizes Rab35-dependent regulation of b1 integrin trafficking. Our results define CLIC4 as a regulator of Rab35 activity and serum-and LPAdependent integrin trafficking.

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“…It is ubiquitously expressed and has been reported to localize to various subcellular compartments, including organelles, the cortical actin cytoskeleton, the plasma membrane, vesicles, and centrosomes, depending on the cell type examined (Chuang et al, 1999;Edwards, 1999;Fernandez-Salas et al, 2002;Proutski et al, 2002;Berryman and Goldenring, 2003;Suh et al, 2004). In addition to inducing anion channel activity, CLIC4 has been implicated in such diverse biological processes as keratinocyte differentiation, apoptosis, receptor trafficking, endothelial vacuole formation, and tubulogenesis (Bohman et al, 2005;Suh et al, 2007;Maeda et al, 2008;Tung et al, 2009;Ulmasov et al, 2009). In Caenorhabditis elegans, the CLIC-like EXC-4 protein is essential for the formation and maintenance of the excretory tube, but the underlying mechanism is not understood (Berry et al, 2003;Berry and Hobert, 2006).…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal Regulation of Chloride Intracellular Channel Protein CLIC4 by RhoA

Ponsioen¹,

Zeijl²,

Langeslag³

et al. 2009

MBoC

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Chloride intracellular channel (CLIC) 4 is a soluble protein structurally related to omega-type glutathione-S-transferases (GSTs) and implicated in various biological processes, ranging from chloride channel formation to vascular tubulogenesis. However, its function(s) and regulation remain unclear. Here, we show that cytosolic CLIC4 undergoes rapid but transient translocation to discrete domains at the plasma membrane upon stimulation of G 13 -coupled, RhoA-activating receptors, such as those for lysophosphatidic acid, thrombin, and sphingosine-1-phosphate. CLIC4 recruitment is strictly dependent on G␣ 13 -mediated RhoA activation and F-actin integrity, but not on Rho kinase activity; it is constitutively induced upon enforced RhoA-GTP accumulation. Membrane-targeted CLIC4 does not seem to enter the plasma membrane or modulate transmembrane chloride currents. Mutational analysis reveals that CLIC4 translocation depends on at least six conserved residues, including reactive Cys35, whose equivalents are critical for the enzymatic function of GSTs. We conclude that CLIC4 is regulated by RhoA to be targeted to the plasma membrane, where it may function not as an inducible chloride channel but rather by displaying Cys-dependent transferase activity toward a yet unknown substrate.

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CLIC4 mediates and is required for Ca2+-induced keratinocyte differentiation

Abstract: and pH of the nucleus, contributes to cell cycle arrest and the specific gene expression program associated with keratinocyte terminal differentiation.

Cited by 54 publications

References 57 publications

S-Nitrosylation Regulates Nuclear Translocation of Chloride Intracellular Channel Protein CLIC4

S-Nitrosylation Regulates Nuclear Translocation of Chloride Intracellular Channel Protein CLIC4

CLIC4 regulates cell adhesion and β1 integrin trafficking

Spatiotemporal Regulation of Chloride Intracellular Channel Protein CLIC4 by RhoA

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