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Background: This study aimed to analyze the role of myelin protein zero-like 3 (MPZL3), a single membrane glycoprotein, in prognosis, tumor immune infiltration, and drug susceptibility in human cancers. Methods: Data regarding MPZL3 were extracted from the TCGA, GTEx, CellMiner, CCLE, TIMER, GSEA, and USCS Xena databases. The expression difference, survival outcomes, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), tumor microenvironment (TME), immune cell infiltration, and drug sensitivity of MPZL3 were analyzed by R language software. Cell proliferation and drug sensitivity tests were applied to analyze the biological role of MPZL3 and drug sensitivities in breast cancer. Results: MPZL3 was highly expressed in most cancer types and correlated with unfavorable survival outcomes in several cancers. TMB, MSI, MMR, DNA methylation, and RNA modification played a significant role in mediating MPZL3 dysregulation in cancers, and MPZL3 was closely linked to CD8+ T cells and CD4+ T immune infiltration. The MPML3 mRNA level was associated with protein secretion, the Notch signaling pathway, and heme metabolism. In addition, drug sensitivity analysis and validation also indicated that MPZL3 expression influenced the sensitivity of therapeutics targeting EGFR, ABL, FGFR, etc. Additionally, MPZL3 overexpression contributed to proliferation and drug sensitivity in different subtypes of breast cancer. Conclusions: This study provides a comprehensive analysis and understanding of the oncogenic roles of the pan-cancer gene MPZL3 across different tumors, including breast cancer. MPZL3 could be a potential prognostic biomarker and therapeutic target for breast cancer. [ABSTRACT FROM AUTHOR]

Receptor tyrosine kinases (RTKs) are recognized as targets of precision medicine in human cancer upon their gene amplification or constitutive activation, resulting in increased downstream signal complexity including heterotypic crosstalk with other RTKs. The Met RTK exhibits such reciprocal crosstalk with several members of the human EGFR (HER) family of RTKs when amplified in cancer cells. We show that Met signaling converges on HER3–tyrosine phosphorylation across a panel of seven MET-amplified cancer cell lines and that HER3 is required for cancer cell expansion and oncogenic capacity in vitro and in vivo. Gene expression analysis of HER3-depleted cells identified MPZL3, encoding a single-pass transmembrane protein, as HER3-dependent effector in multiple MET-amplified cancer cell lines. MPZL3 interacts with HER3 and MPZL3 loss phenocopies HER3 loss in MET-amplified cells, while MPZL3 overexpression can partially rescue proliferation upon HER3 depletion. Together, these data support an oncogenic role for a HER3–MPZL3 axis in MET-amplified cancers. [ABSTRACT FROM AUTHOR]

Summary Current gene expression network approaches commonly focus on transcription factors (TFs), biasing network-based discovery efforts away from potentially important non-TF proteins. We developed proximity analysis, a network reconstruction method that uses topological constraints of scale-free, small-world biological networks to reconstruct relationships in eukaryotic systems, independent of subcellular localization. Proximity analysis identified MPZL3 as a highly connected hub that is strongly induced during epidermal differentiation. MPZL3 was essential for normal differentiation, acting downstream of p63, ZNF750, KLF4, and RCOR1, each of which bound near the MPZL3 gene and controlled its expression. MPZL3 protein localized to mitochondria, where it interacted with FDXR, which was itself also found to be essential for differentiation. Together, MPZL3 and FDXR increased reactive oxygen species (ROS) to drive epidermal differentiation. ROS-induced differentiation is dependent upon promotion of FDXR enzymatic activity by MPZL3. ROS induction by the MPZL3 and FDXR mitochondrial proteins is therefore essential for epidermal differentiation. [ABSTRACT FROM AUTHOR]

Background: This study aimed to analyze the role of myelin protein zero-like 3 (MPZL3), a single membrane glycoprotein, in prognosis, tumor immune infiltration, and drug susceptibility in human cancers., Methods: Data regarding MPZL3 were extracted from the TCGA, GTEx, CellMiner, CCLE, TIMER, GSEA, and USCS Xena databases. The expression difference, survival outcomes, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), tumor microenvironment (TME), immune cell infiltration, and drug sensitivity of MPZL3 were analyzed by R language software. Cell proliferation and drug sensitivity tests were applied to analyze the biological role of MPZL3 and drug sensitivities in breast cancer., Results: MPZL3 was highly expressed in most cancer types and correlated with unfavorable survival outcomes in several cancers. TMB, MSI, MMR, DNA methylation, and RNA modification played a significant role in mediating MPZL3 dysregulation in cancers, and MPZL3 was closely linked to CD8+ T cells and CD4+ T immune infiltration. The MPML3 mRNA level was associated with protein secretion, the Notch signaling pathway, and heme metabolism. In addition, drug sensitivity analysis and validation also indicated that MPZL3 expression influenced the sensitivity of therapeutics targeting EGFR, ABL, FGFR, etc. Additionally, MPZL3 overexpression contributed to proliferation and drug sensitivity in different subtypes of breast cancer., Conclusions: This study provides a comprehensive analysis and understanding of the oncogenic roles of the pan-cancer gene MPZL3 across different tumors, including breast cancer. MPZL3 could be a potential prognostic biomarker and therapeutic target for breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Li, Wang and Shen.)

We have recently reported a mutation within the conserved immunoglobulin V-type domain of the predicted adhesion protein Mpzl3 (MIM 611707) in rough coat ( rc) mice with severe skin abnormalities and progressive cyclic hair loss. In this study, we tested the hypothesis that the human orthologue MPZL3 on chromosome 11q23.3 is a candidate for similar symptoms in humans. The predicted conserved MPZL3 protein has two transmembrane motifs flanking an extracellular Ig-like domain. The R100Q rc mutation is within the Ig-domain recognition loop that has roles in T-cell receptors and cell adhesion. Results of the rc mouse study, 3D structure predictions, homology with Myelin Protein Zero and EVA1, comprehensive database analyses of polymorphisms and mutations within the human MPZL3 gene and its cell, tissue expression and immunostaining pattern indicate that homozygous or compound heterozygous mutations of MPZL3 might be involved in immune-mediated human hereditary disorders with hair loss. [ABSTRACT FROM AUTHOR]