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CLIC1 recruits PIP5K1A/C to induce cell-matrix adhesions for tumor metastasis
Jei-Ming Peng, … , Ming-Chin Yu, Sen-Yung Hsieh
Jei-Ming Peng, … , Ming-Chin Yu, Sen-Yung Hsieh
Published October 20, 2020
Citation Information: J Clin Invest. 2021;131(1):e133525. https://doi.org/10.1172/JCI133525.
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Research Article Cell biology Hepatology Article has an altmetric score of 1

CLIC1 recruits PIP5K1A/C to induce cell-matrix adhesions for tumor metastasis

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Abstract

Membrane protrusion and adhesion to the extracellular matrix, which involves the extension of actin filaments and formation of adhesion complexes, are the fundamental processes for cell migration, tumor invasion, and metastasis. How cancer cells efficiently coordinate these processes remains unclear. Here, we showed that membrane-targeted chloride intracellular channel 1 (CLIC1) spatiotemporally regulates the formation of cell-matrix adhesions and membrane protrusions through the recruitment of PIP5Ks to the plasma membrane. Comparative proteomics identified CLIC1 upregulated in human hepatocellular carcinoma (HCC) and associated with tumor invasiveness, metastasis, and poor prognosis. In response to migration-related stimuli, CLIC1 recruited PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane, where PIP5Ks generate a phosphatidylinositol 4,5-bisphosphate–rich (PIP2-rich) microdomain to induce the formation of integrin-mediated cell-matrix adhesions and the signaling for cytoskeleon extension. CLIC1 silencing inhibited the attachment of tumor cells to culture plates and the adherence and extravasation in the lung alveoli, resulting in suppressed lung metastasis in mice. This study reveals what we believe is an unrecognized mechanism that spatiotemporally coordinates the formation of both lamellipodium/invadopodia and nascent cell-matrix adhesions for directional migration and tumor invasion/metastasis. The unique traits of upregulation and membrane targeting of CLIC1 in cancer cells make it an excellent therapeutic target for tumor metastasis.

Authors

Jei-Ming Peng, Sheng-Hsuan Lin, Ming-Chin Yu, Sen-Yung Hsieh

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Figure 5

CLIC1 directs the formation of cell-matrix adhesions and signaling.

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CLIC1 directs the formation of cell-matrix adhesions and signaling.
(A a...
(A and B) Nascent cell-matrix adhesions in lamellipodia of cells with and without CLIC1 depletion in response to (A) EGF treatment (10 minutes, 100 ng/mL) or (B) exposure to free space (8 hours after wounding). White arrowheads indicate the tips of lamellipodia. Open arrowheads indicate cells with CLIC1 depletion, in which few lamellipodia and nascent adhesions were seen. Scale bar: 10 μm. (C and D) Confocal images for the formation of nascent cell-matrix adhesions 15–30 minutes after cells reseeded on laminin-coated plates. See also Supplemental Figure 5A. (C) Red, CLIC1-RFP; green, talin-GFP, vinculin-GFP, and paxillin-GFP. Box plots: the median and interquartile ranges of the amounts of CLIC1 colocalized with talin, vinculin, and paxillin. (D) Colocalization of CLIC1-GFP but not dCLIC1 (deleted transmembrane domain) or GFP with talin at nascent cell-matrix adhesions. Scale bar: 5 μm. (E) Immunoblots show the effects of silencing CLIC1 on the talin, vinculin, FAK, Src, and actin levels. (F) Coimmunoprecipitation assays using antibodies against talin, FAK, and Src to pull down binding proteins of SK-Hep1 cells with versus without CLIC1 depletion. Immunoblots with antibodies to detect the key components of cell-matrix adhesions. See also Supplemental Figure 5B. Each assay was performed independently at least twice. (G) Cartoons summarize the results from co-IP. (H) CLIC1 selectively required for activation of nascent adhesion–mediated signals. Huh7 cells transfected 2 different clones of siCLIC1 or a control siRNA (siNC). We compared the cells after they had been reseeded (+) or in inactive status (–). Reseeding assays were used to induce the formation of nascent cell-matrix adhesions.

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