Mesothelin

Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.^[5][6]

MSLN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4F3F
Identifiers
Aliases	MSLN, MPF, SMRP, mesothelin
External IDs	OMIM: 601051; MGI: 1888992; HomoloGene: 4249; GeneCards: MSLN; OMA:MSLN - orthologs
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p13.3 Start 760,734 bp[1] End 768,865 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 A3.3 Start 25,967,587 bp[2] End 25,973,352 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube olfactory zone of nasal mucosa right lung upper lobe of left lung germinal epithelium palpebral conjunctiva nasal epithelium pericardium mucosa of paranasal sinus trachea Top expressed in left lung lobe umbilical cord pericardial cavity trachea decidua atrioventricular valve endothelial cell of lymphatic vessel fundus of urinary bladder olfactory epithelium sciatic nerve More reference expression data BioGPS n/a
Gene ontology Molecular function protein binding Cellular component cell surface anchored component of membrane Golgi apparatus membrane extracellular region extracellular space plasma membrane endoplasmic reticulum lumen Biological process pancreas development cell adhesion cell-matrix adhesion post-translational protein modification Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10232 56047 Ensembl ENSG00000102854 ENSMUSG00000063011 UniProt Q13421 Q61468 RefSeq (mRNA) NM_001177355 NM_005823 NM_013404 NM_018857 NM_001356286 NM_001374653 RefSeq (protein) NP_001170826 NP_005814 NP_037536 NP_061345 NP_001343215 Location (UCSC) Chr 16: 0.76 – 0.77 Mb Chr 17: 25.97 – 25.97 Mb PubMed search [3] [4]
Wikidata
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Function

Mesothelin is a 40 kDa protein that is expressed in mesothelial cells.^[7] The protein was first identified by its reactivity with monoclonal antibody K1.^[8] Subsequent cloning studies showed that the mesothelin gene encodes a precursor protein that is processed to yield mesothelin which is attached to the cell membrane by a glycophosphatidylinositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor (MPF). Although it has been proposed that mesothelin may be involved in cell adhesion, its biological function is not known.^[9][10] A knockout mouse line that lacks mesothelin reproduces and develops normally.^[11]

Mesothelin is over expressed in several human tumors, including mesothelioma, ovarian cancer, pancreatic adenocarcinoma,^[7] lung adenocarcinoma,^[12] and cholangiocarcinoma.^[13] Mesothelin binds MUC16 (also known as CA125), indicating that the interaction of mesothelin and MUC16 may contribute to the implantation and peritoneal spread of tumors by cell adhesion.^[14] The region (residues 296-359) consisting of 64 amino acids at the N-terminus of cell surface mesothelin has been identified as the functional binding domain (named IAB) for MUC16/CA125, suggesting the mechanism of mesothelin acting as a MUC16/CA125 functional partner in cancer development.^[15]

A protein structure model of human mesothelin and the binding sites of MUC16 (CA125) and antibodies^[16]

Medical applications

Mesothelin is a tumor differentiation antigen that is normally present on the mesothelial cells lining the pleura,^[17] peritoneum and pericardium.^[7] Since mesothelin is overexpressed in several cancers and is immunogenic, the protein could be exploited as tumor marker or as the antigenic target of a therapeutic cancer vaccine.^[9][18] A 2016 review indicates that some immunotherapeutic strategies have shown encouraging results in early-phase clinical trials.^[19] Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays.^[20] Soluble mesothelin is identified as the extracellular domain of membrane-bound mesothelin shed from tumor cells according to the mass spectrometry analysis of soluble mesothelin purified from cell culture supernatant.^[21]

Assays for blood-borne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed.^[22] Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%).^[23] Blood MPF and mesothelin levels were correlated, with modest accuracy for malignant pleural mesothelioma and lung cancer (sensitivity 74% and 59%, specificity 90% and 86%, respectively for MPF and mesothelin assays).^[24] Circulating mesothelin is reported in nearly all pancreatic cancers,^[25] however the levels in healthy persons often exceed 80 ng/mL (using 40 kD molecular weight as the conversion factor) and to widely overlap the values in the pancreatic cancer patients.^[26] It was noted that the cutoff levels for normal could differ as much as 10-fold among publications, depending on the assay used^[26][24][23] and thus that normal levels must be determined anew when new assays are introduced. Increase of mesothelin-specific antibodies were also detected in the sera of about 40% of patients with mesothelioma and 42% with ovarian cancer, indicating an antibody response to mesothelin was correlated with high expression of mesothelin on tumor cells.^[27]

Human monoclonal antibodies HN1 and SD1 targeting mesothelin have been isolated by phage display.^[28][29] Mitchell Ho and Ira Pastan at the U.S. National Institutes of Health (NIH) generated rabbit monoclonal antibodies targeting rare and poorly immunogenic epitopes of mesothelin, including the C terminus recognized by the YP218 antibody.^[16] The rabbit antibodies have been "humanized" by Ho and Zhang using human immunoglobulin germline framework sequences for CDR grafting based on computational structure modeling.^[30] The CAR-T cells derived from the humanized YP218 antibody (hYP218) effectively inhibit the growth of human xenograft tumors in mice.^[31][32]