Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization

Wang, Xiaoze; Enomoto, Atsushi; Weng, Liang; Mizutani, Yasuyuki; Abudureyimu, Shaniya; Esaki, Nobutoshi; Tsuyuki, Yuta; Chen, Chen; Mii, Shinji; Asai, Naoya; Haga, Hisashi; Ishida, Sumire; Yokota, Kenji; Akiyama, Masashi; Takahashi, Masahide

doi:10.1111/cas.13795

Cited by 35 publications

(36 citation statements)

References 52 publications

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“…Chickadee/profilin binds to actin and affects the formation/remodeling of actin-rich structures [68]. Girdin also binds to actin, as well as the catenin-cadherin complex and the Exo-70 subunit of the exocyst complex, where it has been proposed to coordinate cytoskeleton organization, cell adhesion, membrane trafficking events, and serves as an indicator for poor prognosis with invasive breast cancers [69,70,90,92,93]. Interestingly, girdin and Profilin knockdown embryos exhibit wound repair phenotypes consistent with defects in actin structure assembly/remodeling, actomyosin ring attachment to the overlying plasma membrane, and membrane trafficking.…”

Section: Discussionmentioning

confidence: 99%

Autocrine insulin pathway signaling regulates actin dynamics in cell wound repair

Nakamura

Dominguez

Verboon

et al. 2020

Preprint

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2728 Cells are exposed to frequent mechanical and/or chemical stressors that can compromise the 29 integrity of the plasma membrane and underlying cortical cytoskeleton. The molecular 30 mechanisms driving the immediate repair response that is launched to restore the cell cortex and 31 circumvent cell death are largely unknown. Using drug-inhibition studies and microarray analyses 32 in the Drosophila model, we find that initiation of cell wound repair is dependent on translation, 33 whereas transcription is required for subsequent steps in the process. We identified 253 genes 34 whose expression is up-regulated (80) or down-regulated (173) in response to laser wounding. A 35 subset of these genes were validated using RNAi knockdowns and found to exhibit aberrant 36 actomyosin ring assembly and/or actin remodeling defects. Strikingly, we find that disruption of 37 the canonical insulin signaling pathway leads to abnormal wound repair, and that it controls actin 38 dynamics through the actin regulators Girdin and Chickadee (profilin). Our results provide new 39 insight for understanding how cell wound repair proceeds in healthy individuals and those with 40 diseases involving wound healing deficiencies. 41 42 43 Nakamura et al. 3 4/6/20 4 4/6/20cytoskeleton are remodeled returning them to their pre-wounded composition and organization. 77The mechanisms deployed by the cell for this remodeling have not yet been delineated. 78Previous studies have shown that Ca 2+ is required for the initiation of cell wound repair and 79 serves as a messenger to trigger downstream processes such as transcription: release of internal 80 and/or external Ca 2+ stores activates a number of intracellular pathways resulting in an uptick of 81 gene expression (Fein and Terasaki, 2005; Grembowicz et al., 1999; Joost et al., 2018; Togo, 82 2004). Studies carried out in rat embryos and cultured bovine aortic endothelial cells showed a 83 rapid increase in expression of the Ca 2+ -responsive element containing c-Fos protein as a direct 84 result of plasma membrane damage (Grembowicz et al., 1999; Martin and Nobes, 1992; Verrier 85 et al., 1986). c-Fos, a component of the Activator protein 1 (AP-1), serves as a transcription factor 86 responsible for expressing a number of cytokines and growth factors required to drive the 87 appropriate cellular responses necessary for wound recovery (Shaulian and Karin, 2002; Yates 88 and Rayner, 2002). 89 Interestingly, though the Drosophila syncytial embryo functions under the developmental 90 control of maternally-contributed mRNAs and proteins with minimal levels of zygotic transcription, 91 it is still able to immediately recognize and repair breaches to its cortex. Here we show that 92 translation, rather than transcription, is required for the initial stages of repair in this cell wound 93 repair model. Although transcription does not serve as a "start" signal, disrupting transcription 94 leads to impaired repair in subsequent steps of the process. Using microarrays to assess gene 95 expression cha...

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Section: Discussionmentioning

confidence: 99%

Autocrine insulin pathway signaling regulates actin dynamics in cell wound repair

Nakamura

Dominguez

Verboon

et al. 2020

Preprint

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“…This function in cellcell adhesion is preserved in mammals, and supports collective cell migration [4,5]. Fly and human Girdin also contribute to the coordinated movement of epithelial cells through the organization of supracellular actin cables [3,4].…”

Section: Introductionmentioning

confidence: 90%

“…Mechanistically, Girdin strengthens cell-cell adhesion by promoting the association of core adherens junction components with the actin cytoskeleton [3]. A recent study established that this molecular function is evolutionarily conserved, and that GIRDIN favors the association of β-CATENIN with F-ACTIN [4]. Since knockdown of GIRDIN results in cell dispersion from Caco-2 cell cysts, and since weakening of E-CADHERIN-mediated cell-cell adhesion contributes to cancer cell dissemination and metastasis [64], it is plausible that reduced GIRDIN expression contribute to the formation of secondary tumors and cancer progression.…”

Section: Plos Geneticsmentioning

confidence: 99%

“…The following mutant alleles and transgenic lines were used in this study: Girdin 2 [3], lgl 4 [66], yrt 75 [27], UAS-GFP.nls (Bloomington Drosophila Stock Center [BDSC] Stock No. 4776), and…”

Section: Drosophila Geneticsmentioning

confidence: 99%

“…In Drosophila embryonic epithelia, the protein Girdin stabilizes the ZA by reinforcing the association of the cadherin-catenin complex with the actin cytoskeleton [3]. This function in cellcell adhesion is preserved in mammals, and supports collective cell migration [4,5]. Fly and human Girdin also contribute to the coordinated movement of epithelial cells through the organization of supracellular actin cables [3,4].…”

Section: Introductionmentioning

confidence: 99%

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Girdin is a component of the lateral polarity protein network restricting cell dissemination

et al. 2020

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Epithelial cell polarity defects support cancer progression. It is thus crucial to decipher the functional interactions within the polarity protein network. Here we show that Drosophila Girdin and its human ortholog (GIRDIN) sustain the function of crucial lateral polarity proteins by inhibiting the apical kinase aPKC. Loss of GIRDIN expression is also associated with overgrowth of disorganized cell cysts. Moreover, we observed cell dissemination from GIR-DIN knockdown cysts and tumorspheres, thereby showing that GIRDIN supports the cohesion of multicellular epithelial structures. Consistent with these observations, alteration of GIRDIN expression is associated with poor overall survival in subtypes of breast and lung cancers. Overall, we discovered a core mechanism contributing to epithelial cell polarization from flies to humans. Our data also indicate that GIRDIN has the potential to impair the progression of epithelial cancers by preserving cell polarity and restricting cell dissemination.

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Nanobody‐Engineered Natural Killer Cell Conjugates for Solid Tumor Adoptive Immunotherapy

Gong

Cui

et al. 2021

Small

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Cancer immunotherapy based on natural killer (NK) cells is demonstrated to be a promising strategy. However, NK cells are deficient in ligands that target specific tumors, resulting in limited antitumor efficacy. Here, a glycoengineering approach to imitate the chimeric antigen receptor strategy and decorate NK cells with nanobodies to promote NK‐based immunotherapy in solid tumors is proposed. Nanobody 7D12, which specifically recognizes the human epidermal growth factor receptor (EGFR) that is overexpressed on many solid tumors, is coupled to the chemically synthesized DBCO‐PEG4‐GGG‐NH2 by sortase A‐mediated ligation to generate DBCO‐7D12. The NK92MI cells bearing azide groups are then equipped with DBCO‐7D12 via bioorthogonal click chemistry. The resultant 7D12‐NK92MI cells exhibit high specificity and affinity for EGFR‐overexpressing tumor cells in vitro and in vivo by the 7D12‐EGFR interaction, causing increased cytokine secretion to more effectively kill EGFR‐positive tumor cells, but not EGFR‐negative cancer cells. Importantly, the 7D12‐NK92MI cells also show a wide anticancer spectrum and extensive tumor penetration. Furthermore, mouse experiments reveal that 7D12‐NK92MI treatment achieves excellent therapeutic efficacy and outstanding safety. The authors’ works provide a cell modification strategy using specific protein ligands without genetic manipulation and present a potential novel method for cancer‐targeted immunotherapy by NK cells.

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Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization

Cited by 35 publications

References 52 publications

Autocrine insulin pathway signaling regulates actin dynamics in cell wound repair

Autocrine insulin pathway signaling regulates actin dynamics in cell wound repair

Girdin is a component of the lateral polarity protein network restricting cell dissemination

Nanobody‐Engineered Natural Killer Cell Conjugates for Solid Tumor Adoptive Immunotherapy

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