Cell surface glycoprotein PZR is a major mediator of concanavalin A-induced cell signaling
ABSTRACT PZR is an immunoglobulin superfamily cell surface protein containing a pair of immunoreceptor tyrosine-based inhibitory motifs. As a glycoprotein, PZR displays a strong association with concanavalin A (ConA), a member of the plant lectin family. Treatment of several cell lines with ConA caused tyrosine phosphorylation of a major cellular protein. Immunoblotting and immunoprecipitation studies indicated that this protein corresponded to PZR. Tyrosine phosphorylation of PZR was accompanied by recruitment of SHP-2 and was inhibited by PP1, a selective inhibitor of the Src family tyrosine kinases. Furthermore, c-Src was constitutively associated with PZR and was activated upon treatment of cells with ConA. Moreover, tyrosine phosphorylation of PZR was markedly enhanced in v-Src-transformed NIH-3T3 cells and was predominant in Escherichia coli cells co-expressing c-Src. Expression of an intracellular domain-truncated form of PZR in HT-1080 cells affected cell morphology and had a dominant negative effect on ConA-induced tyrosine phosphorylation of PZR, activation of c-Src, and agglutination of the cells. Together, the data indicate that PZR is a major receptor of ConA and has an important role in cell signaling via c-Src. Considering the various biological activities of ConA, the study of PZR may have major therapeutic implications.
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ABSTRACT: We have previously identified 1 241 regions of somatic copy number alterations (CNAs) in hepatocellular carcinoma (HCC). In the present study, we found that a novel recurrent focal amplicon, 1q24.1-24.2, targets the MPZL1 gene in HCC. Notably, there is a positive correlation between the expression levels of MPZL1 and intrahepatic metastasis of the HCC specimens. MPZL1 can significantly enhance the migratory and metastatic potential of the HCC cells. Moreover, we found that one of the mechanisms by which MPZL1 promotes HCC cell migration is by inducing the phosphorylation and activation of the pro-metastatic protein, cortactin. Additionally, we found that Src kinase mediates the phosphorylation and activation of cortactin induced by MPZL1 overexpression. Taken together, these findings suggest that MPZL1 is a novel pro-metastatic gene targeted by a recurrent region of copy number amplification at 1q24.1-24.2 in HCC.Cell Research advance online publication 3 December 2013; doi:10.1038/cr.2013.158.Cell Research 12/2013; DOI:10.1038/cr.2013.158 · 11.98 Impact Factor
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ABSTRACT: Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding for Shp2, which manifests in congenital heart disease, short stature and facial dysmorphia. The complexity of Shp2 signaling is exemplified by the observation that LEOPARD syndrome (LS) patients possess inactivating PTPN11 mutations yet exhibit similar symptoms to NS. Here, we identify protein zero-related (PZR), a transmembrane glycoprotein, which interfaces with the extracellular matrix to promote cell migration, as a major hypertyrosyl phosphorylated protein in mouse and zebrafish models of NS and LS. PZR hypertyrosyl phosphorylation is facilitated in a phosphatase-independent manner by enhanced Src recruitment to NS and LS Shp2. In zebrafish, PZR overexpression recapitulated NS and LS phenotypes. PZR was required for zebrafish gastrulation in a manner dependent upon PZR tyrosyl phosphorylation. Hence, we identify PZR as a NS and LS target. Enhanced PZR-mediated membrane recruitment of Shp2 serves as a common mechanism to direct overlapping pathophysiological characteristics of these PTPN11 mutations.Molecular and Cellular Biology 05/2014; 34(15). DOI:10.1128/MCB.00135-14 · 5.04 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer mortality worldwide. It is noted that metastasis is a fundamental biological behavior of HCC and the main cause of treatment failure. The identification of somatic alterations and their specific inhibitors may contribute to reduce side effects and prolong patient survival in HCC. Chromosomal copy number alterations (CNAs) are important subclasses of somatic mutations and can be used as an effective method of identifying driver genes with causal roles in carcinogenesis. Jia et al. identified a novel recurrent focal amplicon, 1q24.1-24.2, targets the MPZL1 gene in HCC. They also found that MPZL1 may recruit the SHP-2 and subsequently activate/phosphorylate Src kinase at Tyr426, promoting phosphorylation of cortactin and migration of HCC cells. It is noted that phosphorylation of Tyr416 in the activation loop of the kinase domain up-regulates enzyme activity of Src. In addition, the active state of c-Src, p-Tyr416-c-Src, is an independent prognostic marker of poor patient survival in HCC. Therefore, c-Src signaling may be a druggable target and c-Src targeted therapy may improve patient outcome in this specific subtype of HCC patient with a gain of the recurrent focal amplicon, 1q24.1-24.2.04/2014; 3(2):87-90. DOI:10.3978/j.issn.2304-3881.2014.02.06