Exo70 Isoform Switching upon Epithelial-Mesenchymal Transition Mediates Cancer Cell Invasion

Lu, Hezhe; Liu, Jianglan; Liu, Shujing; Zeng, Jingwen; Ding, Deqiang; Carstens, Russ P.; Cong, Yu‐Sheng; Xu, Xiaowei; Guo, Wei

doi:10.1016/j.devcel.2013.10.020

Cited by 63 publications

(83 citation statements)

References 72 publications

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“…This Exo70 isoform cannot interact with the Arp2/3 complex and fails to stimulate cell motility (Warzecha et al, 2010;Lu et al, 2013). Isoform switching of Exo70 takes place during epithelial-to-mesenchymal transition, and is implicated in breast cancer metastasis (Lu et al, 2013). Exo70 was also found to be the most diversified subunit of the exocyst complex in plants -many of them have dozens of Exo70 paralogues per genome.…”

Section: Functional Diversification Of the Exocystmentioning

confidence: 99%

“…During epithelialization, epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) mediate the generation of a particular isoform of Exo70 (also known as Exo70-E; Lu et al, 2013) that differs from other Exo70 isoforms by a 23-amino-acid insertion. This Exo70 isoform cannot interact with the Arp2/3 complex and fails to stimulate cell motility (Warzecha et al, 2010;Lu et al, 2013). Isoform switching of Exo70 takes place during epithelial-to-mesenchymal transition, and is implicated in breast cancer metastasis (Lu et al, 2013).…”

Section: Functional Diversification Of the Exocystmentioning

confidence: 99%

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The Exocyst at a Glance

Guo

2015

Journal of Cell Science

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The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. Spatial and temporal control of exocytosis through the exocyst has a crucial role in a number of physiological processes, such as morphogenesis, cell cycle progression, primary ciliogenesis, cell migration and tumor invasion. In this Cell Science at a Glance poster article, we summarize recent works on the molecular organization, function and regulation of the exocyst complex, as they provide rationales to the involvement of this complex in such a diverse array of cellular processes.

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Section: Functional Diversification Of the Exocystmentioning

confidence: 99%

Section: Functional Diversification Of the Exocystmentioning

confidence: 99%

The Exocyst at a Glance

Guo

2015

Journal of Cell Science

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“…In humans, EXO70 mediates the trafficking of the glucose transporter Glut4 to the plasma membrane that is stimulated by insulin and involved in the development of diabetes (13). A specific isoform of human EXO70 is also involved in cancer cell invasion (13)(14)(15). Endosidin2 (ES2) was identified from a plantbased chemical screen as an inhibitor of trafficking.…”

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confidence: 99%

Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis

Zhang

Brown

Ven

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. This study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.T he EXO70 (exocyst component of 70 kDa) protein is a component of the evolutionarily conserved octameric exocyst complex that tethers post-Golgi vesicles to the plasma membrane before SNARE-mediated membrane fusion (1). As an important component of the exocyst complex that mediates exocytosis, EXO70 regulates, for example, neurite outgrowth, epithelial cell polarity establishment, cell motility, and cell morphogenesis in animal cells (2-6). In plants, EXO70 proteins participate in polarized pollen tube growth, root hair growth, deposition of cell wall material, cell plate initiation and maturation, defense, and autophagy (7-12). In humans, EXO70 mediates the trafficking of the glucose transporter Glut4 to the plasma membrane that is stimulated by insulin and involved in the development of diabetes (13). A specific isoform of human EXO70 is also involved in cancer cell invasion (13-15). Endosidin2 (ES2) was identified from a plantbased chemical screen as an inhibitor of trafficking. We demonstrate that the target of ES2 is the EXO70 subunit of the exocyst and that ES2 is active in plants and mammalian systems. Significantly, no inhibitor of the exocyst complex has been reported, yet such compounds could be important for understanding the basic mechanisms of exocyst-mediated processes, for modifying secretion in biotechnological applications, and for the development of potential new drugs with higher affinity and more potent activity to control exocyst-related diseases. Results ES2 InhibitsTrafficking to the Plasma Membrane. ES2 is a previously identified plant endomembrane trafficking disruptor (Fig. 1A) that inhibits polarized growth of pollen tubes in a dose-dependent manner (Fig. S1 A and B) (16). Arabidopsis seedlings grown on media containing ES2 have shorter roots and fewer and shorter root hairs and are less sensitive to gravity stimulation (Fig. S1 C-G). ES2 disrupted the trafficking of proteins that are actively recycled between the plasma membrane and endosome...

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“…Ewald and colleagues found that tumor cells including cytokeratin 14 had greater invasive ability [13]. Guo and colleagues found that Exo70 affected cell structure and movement by bending the cell membrane, which then impacted the cell migration and invasion of a tumor [14]. However, these studies did not incorporate the effects of the surrounding host tissue.…”

Section: Introductionmentioning

confidence: 99%

Tumor proliferation and diffusion on percolation clusters

et al. 2016

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We study in silico the influence of host tissue inhomogeneity on tumor cell proliferation and diffusion by simulating the mobility of a tumor on percolation clusters with different homogeneities of surrounding tissues. The proliferation and diffusion of a tumor in an inhomogeneous tissue could be characterized in the framework of the percolation theory, which displays similar thresholds (0.54, 0.44, and 0.37, respectively) for tumor proliferation and diffusion in three kinds of lattices with 4, 6, and 8 connecting near neighbors. Our study reveals the existence of a critical transition concerning the survival and diffusion of tumor cells with leaping metastatic diffusion movement in the host tissues. Tumor cells usually flow in the direction of greater pressure variation during their diffusing and infiltrating to a further location in the host tissue. Some specific sites suitable for tumor invasion were observed on the percolation cluster and around these specific sites a tumor can develop into scattered tumors linked by some advantage tunnels that facilitate tumor invasion. We also investigate the manner that tissue inhomogeneity surrounding a tumor may influence the velocity of tumor diffusion and invasion. Our simulation suggested that invasion of a tumor is controlled by the homogeneity of the tumor microenvironment, which is basically consistent with the experimental report by Riching et al. as well as our clinical observation of medical imaging. Both simulation and clinical observation proved that tumor diffusion and invasion into the surrounding host tissue is positively correlated with the homogeneity of the tissue.

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Exo70 Isoform Switching upon Epithelial-Mesenchymal Transition Mediates Cancer Cell Invasion

Cited by 63 publications

References 72 publications

The Exocyst at a Glance

The Exocyst at a Glance

Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis

Tumor proliferation and diffusion on percolation clusters

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