Alternative titles; symbols
HGNC Approved Gene Symbol: MPZL1
Cytogenetic location: 1q24.2 Genomic coordinates (GRCh38) : 1:167,721,982-167,791,919 (from NCBI)
The MPZL1 gene encodes at least 3 membrane glycoprotein isoforms, the longest of which contains 2 intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) for interaction with the Src (190090) homology-2 (SH2) domain of SHP2 (PTPN11; 176876). This isoform regulates cell migration in a SHP2-dependent manner. MPZL1 isoforms lacking ITIMs may inhibit the function of full-length MPZL1 (summary by Zannettino et al., 2003).
Protein tyrosine phosphatases (PTPs) have a pivotal role in cell proliferation, differentiation, and transformation. Zhao and Zhao (1998) identified MPZL1, which they called PZR, as a 43-kD hyperphosphorylated membrane glycoprotein that had a specific and near-stoichiometric association with PTPN11. By EST database searching and PCR RACE on kidney, HeLa, and 293 cell cDNA libraries, they isolated a cDNA encoding PZR. The predicted 269-amino acid PZR protein shares 45.8% identity with myelin protein zero (MPZ; 159440). PZR contains an N-terminal signal sequence and a single membrane-spanning segment. The extracellular portion forms an Ig-like domain with potential N-linked glycosylation sites. The intracellular portion contains an ITIM consensus sequence, a motif observed in another potential PTPN11 substrate, PTPNS1 (602461). Northern blot analysis revealed expression of a major 4.0-kb PZR transcript and minor 3.8- and 1.3-kb PZR transcripts in all tissues tested, with highest expression in heart, placenta, kidney, and pancreas.
By PCR of human hematopoietic cell lines, Zannettino et al. (2003) cloned 3 splice variants of PZR, which they called PZR, PZRa, and PZRb. The deduced proteins contain 269, 202, and 209 amino acids, respectively. All have an identical extracellular domain, with a predicted signal peptide cleavage site, an IgV-set domain motif linked by disulphide bridges, 2 potential N-glycosylation sites, and 3 O-glycosylation sites, followed by identical transmembrane regions. The isoforms differ in their C-terminal cytoplasmic domains, with only full-length PZR having 2 ITIMs for binding SHP2. RT-PCR detected variable expression of the 3 variants in human monocytic, stromal, endothelial, and epithelial cells. Differentiation of human U937 promonocytic cells along the monocytic lineage was accompanied by decreased expression of PZRb and increased expression of PZR.
Independently, Zhao and Zhao (2003) identified the PZRb variant, which they called PZR1b. PCR detected variable expression of PZR and PZRb in 20 adult human tissues, 2 fetal tissues, and 2 human cell lines tested. PZR predominated in all adult tissues and in fetal brain, whereas PZRb predominated in fetal liver. Jurkat and HL-60 cells showed robust expression of both variants. Western blot analysis detected deglycosylated PZR and PZRb at apparent molecular masses of approximately 30 and 21 kD, respectively.
Paardekooper Overman et al. (2014) found that Pzr was ubiquitously expressed in mouse and zebrafish. In zebrafish embryos, Pzr was maternally contributed and expressed during and after gastrulation.
Independently, Zannettino et al. (2003) and Zhao and Zhao (2003) determined that the MPZL1 gene has 6 exons and spans 66 kb. Exon 1 contains the translation start codon, and intron 1 spans approximately 43 kb. Zhao and Zhao (2003) identified a CpG island of approximately 800 bp covering exon 1 and the 5-prime flanking region.
By FISH and genomic sequence analysis, respectively, Zannettino et al. (2003) and Zhao and Zhao (2003) independently mapped the MPZL1 gene to chromosome 1q24.
Zhao and Zhao (1998) found that PZR could be dephosphorylated by PTPN11, a positive transducer of growth factor signal transduction, but not by PTPN6 (176883), which has a negative role in hematopoietic cell proliferation.
Using wildtype and Shp2 -/- mouse embryonic fibroblasts, Zannettino et al. (2003) found that full-length human PZR, but not PZRa or PZRb, promoted Shp2-dependent migration over a fibronectin (FN1; 135600) substrate.
Zhao and Zhao (2003) found that PZRb did not interact with SHP2 and that expression of PZRb in HT-1080 cells inhibited both mitogen-induced tyrosine phosphorylation of PZR and SHP2 recruitment to PZR.
Paardekooper Overman et al. (2014) found that morpholino-mediated knockdown of Prz in zebrafish reduced body axis and caused heart edema and craniofacial defects, similar to the effects of Shp2 knockdown in zebrafish. Partial knockdown of Pzr and Shp2 together exacerbated the defects, suggesting that Pzr and Shp2 function in a conserved signaling pathway in zebrafish.
Paardekooper Overman, J., Yi, J.-S., Bonetti, M., Soulsby, M., Preisinger, C., Stokes, M. P., Hui, L., Silva, J. C., Overvoorde, J., Giansanti, P., Heck, A. J. R., Kontaridis, M. I., den Hertog, J., Bennett, A. M. PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice. Molec. Cell. Biol. 34: 2874-2889, 2014. [PubMed: 24865967] [Full Text: https://doi.org/10.1128/MCB.00135-14]
Zannettino, A. C. W., Roubelakis, M., Welldon, K. J., Jackson, D. E., Simmons, P. J., Bendall, L. J., Henniker, A., Harrison, K. L., Niutta, S., Bradstock, K. F., Watt, S. M. Novel mesenchymal and haematopoietic cell isoforms of the SHP-2 docking receptor, PZR: identification, molecular cloning and effects on cell migration. Biochem. J. 370: 537-549, 2003. [PubMed: 12410637] [Full Text: https://doi.org/10.1042/BJ20020935]
Zhao, R., Zhao, Z. J. Identification of a variant form of PZR lacking immunoreceptor tyrosine-based inhibitory motifs. Biochem. Biophys. Res. Commun. 303: 1028-1033, 2003. [PubMed: 12684038] [Full Text: https://doi.org/10.1016/s0006-291x(03)00484-4]
Zhao, Z. J., Zhao, R. Purification and cloning of PZR, a binding protein and putative physiological substrate of tyrosine phosphatase SHP-2. J. Biol. Chem. 273: 29367-29372, 1998. [PubMed: 9792637] [Full Text: https://doi.org/10.1074/jbc.273.45.29367]