<i>MICAL2</i>is a novel human cancer gene controlling mesenchymal to epithelial transition involved in cancer growth and invasion

Mariotti, Sara; Barravecchia, Ivana; Vindigni, Carla; Pucci, Angela; Balsamo, Michele; Libro, Rosaliana; Senchenko, V. N.; Dmitriev, Alexey A.; Jacchetti, Emanuela; Cecchini, Marco; Roviello, Franco; Lai, Michele; Broccoli, Vania; Andreazzoli, Massimiliano; Mazzanti, Chiara Maria; Angeloni, Debora

doi:10.18632/oncotarget.6577

Cited by 61 publications

(68 citation statements)

References 43 publications

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“…Interestingly, Mical also has ties to several of these Abl-related cancers (Mariotti, et al, 2016; Loria, et al, 2015; Ashida, et al, 2006), so we examined if MICAL might be linked to Abl’s carcinogenic effect. We tested this hypothesis using breast cancer cell lines as a model, because active Abl kinases are required for the invasion, growth, proliferation, and survival of these cancer cells (Ganguly and Plattner, 2012) – and genetic alterations including gene amplifications and mutations in MICAL s have also been found in breast cancer cells/patient-derived xenografts (Figure S6A; (Eirew, et al, 2015; Rodenhiser, et al, 2008; Lin, et al, 2007; Sjoblom, et al, 2006)).…”

Section: Resultsmentioning

confidence: 99%

Amplification of F-Actin Disassembly and Cellular Repulsion by Growth Factor Signaling

et al. 2017

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SUMMARY Extracellular cues that regulate cellular shape, motility, and navigation are generally classified as growth-promoting (i.e., growth factors/chemoattractants and attractive guidance cues) or growth-preventing (i.e., repellents and inhibitors). Yet, these designations are often based on complex assays and undefined signaling pathways, and thus may misrepresent direct roles of specific cues. Herein, we find that a recognized growth-promoting signaling pathway amplifies the F-actin disassembly and repulsive effects of a growth-preventing pathway. Focusing on Semaphorin/Plexin repulsion, we identified an interaction between the F-actin-disassembly enzyme Mical and the Abl tyrosine kinase. Biochemical assays revealed Abl phosphorylates Mical to directly amplify Mical Redox-mediated F-actin disassembly. Genetic assays revealed Abl allows growth factors and Semaphorin/Plexin repellents to combinatorially increase Mical-mediated F-actin disassembly, cellular remodeling, and repulsive axon guidance. Similar roles for Mical in growth factor/Abl-related cancer cell behaviors further revealed contexts in which characterized positive effectors of growth/guidance stimulate such negative cellular effects as F-actin disassembly/repulsion.

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Section: Resultsmentioning

confidence: 99%

Amplification of F-Actin Disassembly and Cellular Repulsion by Growth Factor Signaling

et al. 2017

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“…EMT is an essential process for embryo formation and development, but also for metastasis (for a review see 123 ). At the same time, MICAL2 was reported as a key protein for cell migration during metastasis in prostate and breast cancer models 115,119,124 and also during changes in endothelial permeability mediated by vascular endothelial growth factor receptor 1 (VEGFR1) in response to Sem3A treatment both in cell culture and in vivo 125 . The three MICAL genes have different subcellular localization and a different pattern of expression in cells and mammalian tissues, with MICAL1 being mostly cytosolic and MICAL2 and 3 enriched in the nuclear fraction, probably due to the presence of a bipartite nuclear localization signal (NLS) downstream of the LIM domain 109,120,121 (Figure 3).…”

Section: Micalmentioning

confidence: 99%

“…MICAL-dependent depolymerization of actin has been involved in processes as diverse as axonal guidance 97,105 , phagocytosis by macrophages 112 , vesicle trafficking 102 , epithelial to mesenchymal transition (EMT) 115–117 , and cancer invasion and metastasis 115,116,118,119 . Three paralogous genes were identified in mammals, named MICAL1–3 97 , with different distribution patterns in embryonic and adult tissues 95,109,120 .…”

Section: Micalmentioning

confidence: 99%

Regulated methionine oxidation by monooxygenases

Manta

Gladyshev

2017

Free Radical Biology and Medicine

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Protein function can be regulated via post-translational modifications by numerous enzymatic and non-enzymatic mechanisms, including oxidation of cysteine and methionine residues. Redox-dependent regulatory mechanisms have been identified for nearly every cellular process, but the major paradigm has been that cellular components are oxidized (damaged) by reactive oxygen species (ROS) in a relatively unspecific way, and then reduced (repaired) by designated reductases. While this scheme may work with cysteine, it cannot be ascribed to other residues, such as methionine, whose reaction with ROS is too slow to be biologically relevant. However, methionine is clearly oxidized in vivo and enzymes for its stereoselective reduction are present in all three domains of life. Here, we revisit the chemistry and biology of methionine oxidation, with emphasis on its generation by enzymes from the monooxygenase family. Particular attention is placed on MICALs, a recently discovered family of proteins that harbor an unusual flavin-monooxygenase domain with an NADPH-dependent methionine sulfoxidase activity. Based on the structural and kinetic information we provide a rational framework to explain MICAL mechanism, inhibition, and regulation. Methionine residues that are targeted by MICALs are reduced back by methionine sulfoxide reductases, suggesting that reversible methionine oxidation may be a general mechanism analogous to the regulation by phosphorylation by kinases/phosphatases. The identification of new enzymes that catalyze the oxidation of methionine will open a new area of research at the forefront of redox signaling.

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“…FAD domain contains flavin mono‐oxygenase activity and is responsible for majority of MICAL1's function 9. Recently, overexpression of MICAL2 and MICAL‐L2, the other members of MICAL family, has been confirmed to be related to multiple invasive phenotype of cancer cells such as increased motility, proliferation, as well as inducing epithelial‐to‐mesenchymal transition (EMT) 10, 11. Domain architecture of MICAL1 is closely related to Drosophila MICAL4; however, to date, only a few reports characterizing the functions of MICAL1 in human cancer progression have been published.…”

Section: Introductionmentioning

confidence: 99%

MICAL1 facilitates breast cancer cell proliferation via ROS‐sensitive ERK/cyclin D pathway

Deng

Wang

Zhao

et al. 2018

J Cellular Molecular Medi

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Molecule interacting with CasL 1 (MICAL1) is a multidomain flavoprotein mono‐oxygenase that strongly involves in cytoskeleton dynamics and cell oxidoreduction metabolism. Recently, results from our laboratory have shown that MICAL1 modulates reactive oxygen species (ROS) production, and the latter then activates phosphatidyl inositol 3‐kinase (PI3K)/protein kinase B (Akt) signalling pathway which regulates breast cancer cell invasion. Herein, we performed this study to assess the involvement of MICAL1 in breast cancer cell proliferation and to explore the potential molecular mechanism. We noticed that depletion of MICAL1 markedly reduced cell proliferation in breast cancer cell line MCF‐7 and T47D. This effect of MICAL1 on proliferation was independent of wnt/β‐catenin and NF‐κB pathways. Interestingly, depletion of MICAL1 significantly inhibited ROS production, decreased p‐ERK expression and unfavourable for proliferative phenotype of breast cancer cells. Likewise, MICAL1 overexpression increased p‐ERK level as well as p‐ERK nucleus translocation. Moreover, we investigated the effect of MICAL1 on cell cycle‐related proteins. MICAL1 positively regulated CDK4 and cyclin D expression, but not CDK2, CDK6, cyclin A and cyclin E. In addition, more expression of CDK4 and cyclin D by MICAL1 overexpression was blocked by PI3K/Akt inhibitor LY294002. LY294002 treatment also attenuated the increase in the p‐ERK level in MICAL1‐overexpressed breast cancer cells. Together, our results suggest that MICAL1 exhibits its effect on proliferation via maintaining cyclin D expression through ROS‐sensitive PI3K/Akt/ERK signalling in breast cancer cells.

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MICAL2is a novel human cancer gene controlling mesenchymal to epithelial transition involved in cancer growth and invasion

Cited by 61 publications

References 43 publications

Amplification of F-Actin Disassembly and Cellular Repulsion by Growth Factor Signaling

Amplification of F-Actin Disassembly and Cellular Repulsion by Growth Factor Signaling

Regulated methionine oxidation by monooxygenases

MICAL1 facilitates breast cancer cell proliferation via ROS‐sensitive ERK/cyclin D pathway

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