Advances in Mig6 gene in tumor research

Ye-Min-Xiao Zeng, An Yan, Zhong-Gang Wu, Wen-Jie Zeng, Huai-Yuan Zheng, Xiu-Ling Wei , Shi-Bo Zhao, , Zi-Hui Liu

1College of clinical, Youjiang Medical University for Nationalities, Baise 533000, China.2College of Medical Laboratory, Youjiang Medical University for Nationalities, Baise 533000, China.3Obstetrics and Gynecology, Southwest Hospital Affiliated to Youjiang Medical College for Nationalities/People's Hospital of Baise, Baise 533000, China.4Graduate School, Youjiang Medical University for Nationalities, Baise 533000, China.5General Surgery, First People's Hospital of Fangchenggang, Fangchenggang 538000, China.6College of Clinical Medicine, Guilin Medical University, Guilin 541000, China.7Hematology, First People's Hospital of Fangchenggang, Fangchenggang 538000, China.

Background

Mitogen-inducible gene 6 (Mig6), also known as RALT or gene 33, is a multiadaptive protein implicated in the regulation of RTK and stress signaling1-3.In recent years, the negative control of RTK signaling has piqued the interest of researchers.with an increasing number of negative feedback regulators of tyrosine kinase (Receptor Protein Tyrosine Kinase, RTK).Although several commonly used inhibitors have been identified at this stage, this merely emphasizes the significance of signal attenuation and regulation for proper signal output.However, the mechanisms of their action are not well understood, especially those in vivo function and metabolic expression.

In this paper, we review the in vivo research on various tumor aspects of Mig6 related to endogenous epidermal growth factor receptor (EGFR), considering the structure and biological properties of Mig6, to provide references and ideas for further research on the relationship between Mig6 and tumors.

Structure and biological properties of the gene of Mig6

The Mig6 gene chromosomal locus (1p36.12-33) is found in the 1p36.1-3 area, which has been linked to a high rate of allelic loss in human malignancies.Its encoded protein may function as a backbone bridging protein to regulate intracellular signaling.Intracellularly, the Mig6 gene increases its protein expression in response to growth factors, hormones, and various stress stimuli, which in turn interacts with the receptor itself or its downstream signaling molecules in various signaling pathways through its different functional fragments(CRIB region, proline-rich region, 14-3-3 protein binding region and ERB binding region) to activate or inhibit signaling pathways [1].PtdIns (4, 5) P2, a phosphatidylinositol 4, 5-bisphosphate(PIPKγi5)-producing enzyme, was found by Sun Ming et al.[2] to stabilize the expression of the Mig6 gene.When PIPKγi5 was decreased, EGFR-mediated cell signaling was greatly amplified and extended.The proteasomal degradation of Mig6 proteins was greatly accelerated in the absence of PIPKγi5 deletion, although this had no effect on the mRNA levels of Mig6.Higher proliferation and defective differentiation of epidermal keratin-forming cells, increased incidence of tumor lesions, and greater vulnerability to carcinogen-induced papillomas and melanomas have all been reported in the literature.In addition, Mig6 is decreased in a range of human tumor cells from various tissues and in psoriasis, suggesting an effect in other neoplastic diseases and psoriasis.

Biological function of Mig6

When external stimuli including growth hormones, cytokines, and stress factors are present, Mig6 can be activated via transcription.The expression in mammalian cell lines and RNA interference-mediated studies have shown that Mig6 can attenuate the transcriptional induction by EGFR, (Histidine-rich Glycoprotein-b, HRG-b) and Hepatocyte Growth Factor (HGF) 2, 3, 6-8 induced mitogenic signaling.Through the binding of Mig6 to the ErbB receptor,overexpression of Mig6 in vitro inhibits ErbB autophosphorylation and reduces MAPK-3, 7, 9 activity.Mig6 is closely associated with a variety of common human malignancies.There is evidence that Mig6 plays an important role in cell cycle progression and has tumor-suppressive effects, according to the results of Mari Sasaki et al[3].Mig6 loss causes cells to enter mitosis more quickly and exit it more slowly due to prolonged and premature activation of CDK1, a key regulator of mitotic progression in G2/M and mid-to-late-stage transitions.CDK1 inhibition upon DNA damage and G2/M cell cycle arrest are likewise dependent on Mig6.Cdk1's phosphorylation on WEE1-targeted Tyr15 residues is reduced when Mig6 is deleted.In order to inhibit CDK1 activity, Mig6 attaches to WEE1 and blocks the recruitment of the TrCP-SCF E3 ubiquitin ligase and WEE1.Mig6-segment1 and Mig6-segment2 were examined by Yue Zhang et al [4].for their role in binding to EGFR.In order to suppress EGFR,Mig6 must phosphorylate Y394 on Mig6-segment2 by mig6.To better understand how Mig6-segment2 interacts with EGFR, the team turned to molecular dynamics (MD) simulations.A phosphorylation mechanism on Y394 was found, as well as the involvement of critical EGFR residues that connect with the phosphorylated Mig6 segment2.Mig6's inability to reversely inhibit EGFR has also been connected to an unusual L-shaped conformation.Cen L et al [5].studied Mig6 with hexavalent chromium (Cr (VI))-induced DNA damage response (DDR)and revealed the nuclear function of Mig6 that regulates DDR and proposed that Mig6 is a proximal regulator of DDR that plays a role in promoting DNA repair.They also discovered that Mig6's 14-3-3 binding domain regulates its nuclear localization, and that gene 33's chromatin localization is partially regulated by its ErbB binding domain, implying that Mig6 can control c-chromatin Abl's targeting.Park Soo-Yeon [6] and coworkers.Using a yeast two-hybrid screen,identified DNAJB1 as a novel Mig6-interacting protein, and they found that DNAJB1 binds to Mig6 and reduces Mig6 protein levels,which in turn increases EGFR signaling.

The relationship between Mig6 and EFGR and ERBB on tumor

Mig6 causes excessive EGFR activation and poor differentiation of epidermal cells in experiments, increasing susceptibility to chemically induced skin tumor development.Several researchers have shown that the ErbB signaling system, which consists of four proto-oncogene receptor tyrosine kinases ErbB1/EGFR, ErbB2/Her2, ErbB3/Her3, and ErbB4/Her4, plays a key role in normal physiology and cancer.Three hotspot peptides extracted from functional segment 1 (Seg1) of Mig6 S1P1, S1P2, and S1P3 have been observed toIt was demonstrated that the Mig6 peptide inhibits EGFR and binds Her2, Her3, and Her4 and that all exhibit typical selectivity despite the widely different affinities of the peptides for the four ErbB kinases.

Mig6 mechanism of action in tumors

Epithelial carcinoma

EGF receptors and their ligands have been found to be elevated in epithelial carcinomas associated with increased Mig6 activity.EGFR signaling in the epidermis, which is present in the cytoplasm and plasma membranes of basal keratin-forming cells, can be modulated by Mig6, according to studies.An EGFR-dependent oncogene, Mig6, is a novel tumor suppressor with distinct negative regulation of EGFR signaling in skin development.

Non-alcoholic steatohepatitis and hepatocellular carcinoma

Kokuda et al [7].investigated the mechanisms of nonalcoholic steatohepatitis (NASH) and NASH-induced hepatocellular carcinoma(HCC), and They discovered that in the livers of animals with NASH and human HCC tissues, EGFR signaling was hyperactivated.In contrast, Mig6 was discovered to be a new tumor suppressor with EGFR-dependent oncogenic effects, as well as an unique negative regulator of EGFR signaling in skin morphogenesis.Therefore, Mig6 is worth exploring in the pathogenesis of NASH, and HCC.Chen Xiao et al [8].used real-time fluorescence quantitative polymerase chain reaction technique to observe the effect of myocyte enhancer factor 2D (MEF2D) on the proliferation and migration of hepatocellular carcinoma cells PLC/PRF5 and SMMC7721 to investigate whether it played a role through the negative regulation of Mig6 expression and concluded that MEF2D in hepatocellular carcinoma cells PLC/PRF5 and SMMC7721.Thus, the expression of MEF2D and Mig6 in PLC/PRF5 and SMMC7721 were negatively correlated, and MEF2D probably promoted the proliferation and migration of PLC/PRF5 and SMMC7721 by negatively regulating the expression of Mig6 in hepatocellular carcinoma cells.

Invasive breast cancer

In invasive breast cancer, EGFR signaling is a tightly regulated process, with a delicate balance between receptor activation and inactivation (IBC).Didier Meseure et al [9].explored the posttranslational EGFR transport molecules associated with the EGFR regulatory pathway by Mig6.Mig6 was measured at the mRNA level in 440 IBCs and at the protein level in 88 IBCs using real-time quantitative RT-PCR and immunohistochemistry.The results obtained by RT-PCR showed that MDGI, predominantly expressed at 25.7% in IBCs, suggesting that altered expression of negative EGFR post-translational regulators in EGFR may is possible.Mig6 expression status may also be a potentially useful biomarker in targeted EGFR therapy.Breast cancer with HER2 status has been identified as a therapeutic target for the human epidermal growth factor receptor 2(EGFR2 or HER2), according to this theory.Mig6 fragments that interact with EGFR crystals were grafted onto the breast cancer protein HER2 by Xiao-Dong Yu et al [10], who believe that this will impair HER2 dimerization and so impede kinase activity.

Lung cancer

Park Soyoung et al [11].employed single-cell RNA sequencing to examine gene expression profiles between chronically exposed BEAS-2B lung epithelial cells chronically treated to sublethal levels of Cr (VI) and the findings identified 83 differentially expressed genes.There were a lot of changes in genes that deal with cell adhesion,antioxidant stress, protein ubiquitination, the transition from epithelial to mesenchymal cells, and WNT signaling.CRISPR/cas9-mediated deletion of Mig6 was one of these things.Mig6 removal and/or exposure to Cr (VI) did not change cell morphology in any way.However, the deletion of Mig6 led to a small but significant drop in cell growth in the G2/M phase of the cell cycle, regardless of whether the cells were exposed to Cr (VI).Mig6 deletion also had a big impact on cell growth.Cr (VI) exposure wiped out the differences in cell growth between the two genotypes.The Mig6 deletion also had a big effect on cell migration.The data suggest that when Mig6 is removed and chronic exposure to Cr (VI) is long-term, the gene expression patterns and phenotypes of lung epithelial cells are similar to those of cells that have been damaged.Dephosphorylated Mig6 fragment 2 peptide can be transformed from non-binding to weak binding and then to moderate binding by the phosphorylation and the cycle, respectively, Li Na et al [12].implemented computational modeling and investigation of intermolecular interactions between the EGFR structural domain and the Mig6 fragment 2 peptide.In the linear dephosphorylated peptide, there was no binding to the kinase,and additional phosphorylation or cyclization could confer low or moderate affinity to the peptide.On the other hand, Xiao-Dong Yu et al [10].looked at interrupting dimerization and hence kinase inactivation by binding the activation interface of EGFR kinase.Mig6 fragment 1 and 2 are two isolated parts of Mig6 that they used to interact with EGFR.Computer modeling and analysis of the interactions between the EGFR kinase structural domain and the Mig6 fragment 2 peptides showed that the peptide is folded into a double-stranded "-fold" with a -strand 1 and -strand2.Only -strand 2 can interact directly with the EGFR activation loop, while -strand 1 is separated from the kinase.The C-terminal island in -strand 2 is mostly in charge of peptide binding.This island is part of Mig6 fragment 2.It has a weak affinity for the kinase domain of the EGFR.The shortened peptide's EGFR affinity was improved by phosphorylating Tyr394 and Tyr395 and by mutating additional residues.The researchers next synthesized and purified three different variants of the truncated peptide (phosphorylated and dephosphorylated peptides, and a double point mutant), with their affinity for the human EGFR protein kinase assessed by fluorescence anisotropy titration.Fluorescence anisotropy titration is used to make structural domain recombinant protein.Phosphorylation and mutation could make the peptides less and more likely to be used, which shows that computational analysis and real-world tests are in good agreement.

Endometrial cancer

H Ando et al [13].investigated the role of Mig6 in progestin-mediated inhibition of endometrial epithelial growth.Following medroxyprogesterone acetate treatment, Mig6 immunohistochemical expression increased in normal endometrium from early to mid-secretory phase forward.EC cell viability decreases when progesterone (P4) is given to progesterone receptor (PR)-positive cells,and Mig6 messenger RNA (mRNA) and protein synthesis is triggered.To show that Mig6 is an important downstream component of PR-mediated growth inhibition, we silenced it using siRNA and reversed the P4-mediated reduction in EC cell viability.The addition of three HDAC inhibitors (panobinostat, LBH589; trigonellin A, TSA;suberoylanilide isohydroxamic acid, SAHA) reduced EC cell viability and upregulated PR and Mig6 expression, and the addition of these LBH589 and meproterone acetate lowered EC cell viability and enhanced apoptosis in a synergistic manner.These findings imply that LBH589 has the potential to operate as a progestin enhancer by upregulating PR and Mig6, and that increase of Mig6 expression significantly reduces endometrial cancer proliferation and invasion.

Melanoma

Melanoma of the skin is frequently caused by mutations in the neuroblastoma RAS viral oncogene homolog (NRAS).One of the best-known downstream effectors of the guanosine triphosphatebinding protein (NRAS) known is RAF, which leads to activation of MEK/ERK1/2 signaling in response to mitogen activation.Mig6 was found to be a negative regulator of epidermal growth factor-induced signaling, cell migration, and invasion by Ha Linh Vu et al [14].Increased Mig6 depletion leads to increased migration and invasion,while increased Mig6 expression leads to decreased migration and invasion.As a result, a decrease in Mig6 in MEK-inhibited NRAS melanomas, particularly in response to EGF stimulation, may promote migration and invasiveness.

Conclusion

The Mig6 locus is a gene locus inextricably linked to human carcinogenesis as an oncogene that generates oncogenic signals through the loss of negative feedback regulation of RTK, thereby inhibiting tumor development.The expression of Mig6 is to be significantly decreased in various tumors, including epithelial,hepatocellular, and lung cancers, suggesting that the expression of Mig6 at cancer sites can be regulated at the molecular targeting level to inhibit tumor development, which provides a new direction for the study of anti-tumor drugs.However, the mechanism of action of Mig6 and RTK negative feedback regulators is not clearly elaborated at present, and further confirmation of how Mig6 participates in the regulation of RTK signaling and reflects the results of signal regulation from tumor development is needed, and the study of the mechanism of action of both has great significance for molecularly targeted cancer therapy.