Figure 3 - uploaded by Saskia M Herbst
Content may be subject to copyright.
Schematic illustration of the hypothetical, physiological (A), and pathological (C-D) LPP signaling in human neoplasia. (A) Physiological LPP signaling: LPP permanently shuttles from cytosol into the nucleus and back, thereby transducing signals from the cell surface to the transcription machinery and possibly vice versa. (B) Abnormal LPP signaling through formation of fusion proteins with altered transcriptional signature. As an example, the most common fusion protein of the truncated HGMA2 with the LIM domains of LPP is shown. (C) LPP overexpression leads to enhanced and possibly changed transcription of LPP target genes. (D) Overexpression of LPP binding partners: overexpression of, for example, LASP-1 in tumor cells may lead to enhanced protein binding to LPP, increased nuclear transportation of the shuttle partners, and potentially pathophysiological gene regulation.
Source publication
Integrating signals from the extracellular matrix through the cell surface into the nucleus is an essential feature of metazoan life. To date, many signal transducers known as shuttle proteins have been identified to act as both a cytoskeletal and a signaling protein. Among them, the most prominent representatives are zyxin and lipoma preferred (tr...
Contexts in source publication
Context 1
... 2) and, as such, could be used as promising novel drug targets owing to their unique presence in such tumors and absence in normal tissue. Interestingly, all these tumor-specific fusion proteins, composed of AT hooks from other pro- teins, are mainly localized within the nucleus [22] and possibly con- tribute to altered LPP transcriptional targeting [63,64] (Figure 3B). ...
Context 2
... it is tempting to speculate that overexpression of LPP could cause an up-regulation of PEA3 targets such as MMPs result- ing in an increased invasion and metastasis potential ( Figure 3C ). In support of this hypothesis, nonmetastatic breast cancer cells become metastatic when PEA3 is ectopically overexpressed [44,45]. ...
Context 3
... it was specu- lated that LASP-1 might bind to shuttle proteins such as zyxin and LPP to use their transportation potential into the nucleus [2]. Hypo- thetically, overexpression of LPP binding partners such as LASP-1 in human neoplasia could interfere with normal LPP signaling, resulting in an altered transcriptional signature of LPP that in turn could con- tribute to tumorigenesis ( Figure 3D). A summary of the putative roles of LPP binding partners in human cancer is depicted in Table 2. ...
Citations
... Results from 1469 blood samples were combined with co-expression analyses to give priority to causative genes, from different blood immune cell populations. Data from pathways and tissue-specific expression analyses on these genes identified a role in CeD pathogenesis for Lipoma-Preferred Partner (LPP) [18][19][20], C1ORF106 (C1 Orfan 106), ARGHAP31 [21] and Protein Tyrosine Phosphatase Receptor Type K (PTPRK) genes, which play a role in actin-cytoskeleton rearrangement, cell-cell adhesion and in the Epidermal Growth factor (EGF)/EGF Receptor (EGFR) pathway activation [17,22]. PTPRK, an EGFR phosphatase, is reduced in CeD biopsies respect to controls [17,23]. ...
Background & aims:
Celiac disease (CeD) is an immune-mediated enteropathy triggered in genetically susceptible (HLA-DQ2/8) individuals by a group of wheat proteins and related prolamins from cereals. The celiac intestine is characterized by an inversion of the differentiation/proliferation program of the enterocytes, with an increase in the proliferative compartment and crypt hyperplasia, which are the mechanisms that regulate the increased proliferation in CeD that arenot completely understood.The aim of this study is to understand the role of Protein Tyrosine Phosphatase Receptor Type K (PTPRK), a nodal phosphatase that regulates EGFR activation in the proliferation of the enterocytes from CeD biopsies and organoids.
Methods:
The levels of PTPRK were evaluated by RT PCR, western blot (WB) and immunofluorescence techniques in intestinal biopsies and organoids from CeD patients and controls. Additionally, pEGFR and pERK were evaluated by WB and proliferation by BrdU incorporation. PTPRK si-RNA was silenced in CTR organoids and was overexpressed in CeD organoids.
Results:
PTPRK was reduced in Gluten Containing Diet-Celiac Disease (GCD-CeD) and Potential-Celiac Disease(Pot-CeD) biopsies (p < 0.01-p < 0.05) whereas pEGFR (p < 0.01 p < 0.01), pERK (p < 0.01 p < 0.01) and proliferation were increased. (p < 0.05 p < 0.05) respect to the controls.The CeD organoids reproduced these same alterations. Silencing of PTPRK in CTR organoids increased pEGFR, pERK and proliferation. The overexpression of PTPRK in CeD organoids reduced pEGFR, pERK and proliferation.
Conclusions:
modulation of PTPRK levels can reduce or increase pEGFR, pERK and proliferation in CeD or CTR organoids, respectively. The CeD organoids can be a good model to study the mechanisms of the disease.
... Lipoma-preferred partner (LPP) is located at chromosome 3q27-q28, owned by the zyxin family of proteins (Ngan et al., 2018). It is primarily expressed in the cell periphery of focal adhesion, thus participating in cytoskeletal organization, cell motion, and mechanosensing (Grunewald et al., 2009). The malignant role of LPP within carcinogenesis has been previously revealed. ...
DEAD-box helicase 27 (DDX27) was previously identified as an important mediator during carcinogenesis, while its role in gastric cancer (GC) is not yet fully elucidated. Here, we aimed to investigate the mechanism and clinical significance of DDX27 in GC. Public datasets were analyzed to determine DDX27 expression profiling. The qRT-PCR, Western blot, and immunohistochemistry analyses were employed to investigate the DDX27 expression in GC cell lines and clinical samples. The role of DDX27 in GC metastasis was explored in vitro and in vivo. Mass spectrometry, RNA-seq, and alternative splicing analysis were conducted to demonstrate the DDX27-mediated molecular mechanisms in GC. We discovered that DDX27 was highly expressed in GCs, and a high level of DDX27 indicated poor prognosis. An increased DDX27 expression could promote GC metastasis, while DDX27 knockdown impaired GC aggressiveness. Mechanically, the LLP expression was significantly altered after DDX27 downregulation, and further results indicated that LPP may be regulated by DDX27 via alternative splicing. In summary, our study indicated that DDX27 contributed to GC malignant progression via a prometastatic DDX27/LPP/EMT regulatory axis.
... Each of the above-mentioned partners is involved in different cell functions and all have been implicated in tumor development. LPP belongs to the zyxin family of LIM domain proteins, has focal adhesion capacity, is a transcription activator, interacts with various proteins through its numerous protein-protein interactions domains, and is known to play a role in many biological and cellular processes (69,(73)(74)(75). In a secondary acute myeloid leukemia with a t(3;11)(q28;q23) chromosomal translocation, LPP fused to lysine methyltransferase 2A (KMT2A, formerly MLL) generating a KMT2A-LPP fusion gene which codes for a chimeric protein containing the AT hook of KMT2A and the LIM domains of LPP (76). ...
Background/aim:
Chimeras involving the high-mobility group AT-hook 2 gene (HMGA2 in 12q14.3) have been found in lipomas and other benign mesenchymal tumors. We report here a fusion of HMGA2 with the nuclear receptor co-repressor 2 gene (NCOR2 in 12q24.31) repeatedly found in tumors of bone and the first cytogenetic investigation of this fusion.
Materials and methods:
Six osteoclastic giant cell-rich tumors were investigated using G-banding, RNA sequencing, reverse transcription polymerase chain reaction, Sanger sequencing, and fluorescence in situ hybridization.
Results:
Four tumors had structural chromosomal aberrations of 12q. The pathogenic variant c.103_104GG>AT (p.Gly35Met) in the H3.3 histone A gene was found in a tumor without 12q aberration. In-frame HMGA2-NCOR2 fusion transcripts were found in all tumors. In two cases, the presence of an HMGA2-NCOR2 fusion gene was confirmed by FISH on metaphase spreads.
Conclusion:
Our results demonstrate that a subset of osteoclastic giant cell-rich tumors of bone are characterized by an HMGA2-NCOR2 fusion gene.
... LPP has been known as a member of the zyxin family of proteins that regulates cytoskeletal organization and cell adhesion and motility. 24 Several studies have demonstrated that LPP served as a proto-oncogene and its overexpression could promote cell invasion and metastasis in multiple malignances. 24,25 These previous results were consistent with our findings that LPP was overexpressed in tumor, and high LPP expression was associated with poor prognosis in GC patients. ...
... 24 Several studies have demonstrated that LPP served as a proto-oncogene and its overexpression could promote cell invasion and metastasis in multiple malignances. 24,25 These previous results were consistent with our findings that LPP was overexpressed in tumor, and high LPP expression was associated with poor prognosis in GC patients. However, to date, the roles of LPP, especially regarding principles of immune response and immune escape in GC, are still unclear. ...
Association of tumor microenvironment and immune checkpoint (e.g. PD-L1) is important for immune escape, impacting chemotherapy and immunotherapy efficacy. We aimed to investigate biomarkers and therapeutic targets against treatment resistance in gastric cancer. Abundances of tumor-infiltrating immune cells were estimated in multiple datasets. Three patient subgroups (A, B and C) were identified based on seven types of PD-L1 and IFN-γ associated immune cells. Patients yielded increased prognosis from subgroup A to C (p = 0.027). Subgroup A was characterized by high activated CD4⁺ memory T cell infiltration while more resting CD4⁺ memory T cells were in subgroup C. Further, a risk score was developed for prognostication. LPP, as the hub gene in subgroup-related regulatory network, was up-regulated (p <0.01) and was associated with high risk score (p <0.001) and poor survival (p <0.05). Bioinformatics analyses and experiments found that LPP expressed restrictively in fibroblasts, and associated with activated CD4⁺ memory T cell infiltration and tumor growth. High-LPP patients yielded less benefits from chemotherapy/immunotherapy, compared with low-LPP group. We finally identified 28 compounds as sensitive drugs for high-LPP patients. Our findings suggested LPP might be a biomarker for treatment response and therapeutic target in gastric cancer.
... LPP is also capable of enhancing expression of PEA3-dependent genes in vitro (Guo et al., 2006) that are involved in neuronal development or mediation of fibroblast growth factor signaling (Roehl and Nüsslein, 2001;Firnberg and Neubüser, 2002;Livet et al., 2002). In addition, PEA3 controls genes encoding certain matrix metalloproteinases (MMP) involved in degradation of the ECM (Grunewald et al., 2009). ETV5 is a member of a PEA3 subfamily and a partner of LPP in controlling transcription. ...
... Originally, LPP was discovered in a subset of lipomas as a fusion protein with high mobility group A2 (HMGA2). This fusion protein, in which the carboxy-terminal LIM domains of LPP are fused to the amino-terminal end of HMGA2, has been shown to facilitate the migration of tumor cells (Grunewald et al., 2009). In the cardiovascular system, modulating the phenotype of vascular SMC and degradation of the ECM are important steps for these cells to migrate from the media to form a sub-endothelial neointima following vascular injury (Owens, 1995). ...
... In the context of tumor progression and spreading, LPP may in fact facilitate the abnormal migratory behavior of cancer cells by playing a regulatory role in the formation and function of invadopodia that promote metastasis (Ngan et al., 2017). When overexpressed in HIVS-125 cells (human SMC line), LPP enhances migration and cell spreading (Jin et al., 2007), and when LPP expression is attenuated, the invasiveness of tumor cells is also decreased (Grunewald et al., 2009). These findings suggest that the mechanosensory and perhaps mechanoregulatory function of LPP can also be employed by such cells in a pathological setting. ...
Arterial hypertension is the leading risk factor for cardiovascular morbidity and mortality worldwide. However, little is known about the cellular mechanisms underlying it. In small arteries and arterioles, a chronic increase in blood pressure raises wall tension and hence stretches, namely, the medial vascular smooth muscle cells (VSMC) but also endothelial cell (EC) to cell contacts. Initially compensated by an increase in vascular tone, the continuous biomechanical strain causes a prominent change in gene expression in both cell types, frequently driving an arterial inward remodeling process that ultimately results in a reduction in lumen diameter, stiffening of the vessel wall, and fixation of blood pressure, namely, diastolic blood pressure, at the elevated level. Sensing and propagation of this supraphysiological stretch into the nucleus of VSMC and EC therefore seems to be a crucial step in the initiation and advancement of hypertension-induced arterial remodeling. Focal adhesions (FA) represent an important interface between the extracellular matrix and Lin11-Isl1-Mec3 (LIM) domain-containing proteins, which can translocate from the FA into the nucleus where they affect gene expression. The varying biomechanical cues to which vascular cells are exposed can thus be rapidly and specifically propagated to the nucleus. Zyxin was the first protein described with such mechanotransducing properties. It comprises 3 C-terminal LIM domains, a leucine-rich nuclear export signal, and N-terminal features that support its association with the actin cytoskeleton. In the cytoplasm, zyxin promotes actin assembly and organization as well as cell motility. In EC, zyxin acts as a transcription factor, whereas in VSMC, it has a less direct effect on mechanosensitive gene expression. In terms of homology and structural features, lipoma preferred partner is the nearest relative of zyxin among the LIM domain proteins. It is almost exclusively expressed by smooth muscle cells in the adult, resides like zyxin at FA but seems to affect mechanosensitive gene expression indirectly, possibly via altering cortical actin dynamics. Here, we highlight what is currently known about the role of these LIM domain proteins in mechanosensing and transduction in vascular cells.
... More recent studies predicted a role in CD pathogenesis for lipoma-preferred partner (LPP), C1ORF106 (C1 Orfan 106), Rho GTPase-activating protein 31 (ARHGAP31) and protein tyrosine phosphatase receptor type K (PTPRK) genes, which play a role in actin cytoskeleton rearrangement, cell-cell adhesion and in epidermal growth factor (EGF)/ EGF receptor (EGFR) pathway activation [21][22][23][24]. Transcripts of ARHGAP31, a Rho-GTPaseactivating protein (GAP) which is required for cell spreading, polarized lamellipodia formation and cell migration, are altered in CD immune cells [24]. ...
Celiac disease (CD) is a frequent intestinal inflammatory disease occurring in genetically susceptible individuals upon gluten ingestion. Recent studies point to a role in CD for genes involved in cell shape, adhesion and actin rearrangements, including a Rho family regulator, Rho GTPase-activating protein 31 (ARHGAP31). In this study, we investigated the morphology and actin cytoskeletons of peripheral monocyte-derived dendritic cells (DCs) from children with CD and controls when in contact with a physiological substrate, fibronectin. DCs were generated from peripheral blood monocytes of pediatric CD patients and controls. After adhesion on fibronectin, DCs showed a higher number of protrusions and a more elongated shape in CD patients compared with controls, as assessed by immunofluorescence actin staining, transmitted light staining and video time-lapse microscopy. These alterations did not depend on active intestinal inflammation associated with gluten consumption and were specific to CD, since they were not found in subjects affected by other intestinal inflammatory conditions. The elongated morphology was not a result of differences in DC activation or maturation status, and did not depend on the human leukocyte antigen (HLA)-DQ2 haplotype. Notably, we found that ARH-GAP31 mRNA levels were decreased while RhoA-GTP activity was increased in CD DCs, pointing to an impairment of the Rho pathway in CD cells. Accordingly, Rho inhibition was able to prevent the cytoskeleton rearrangements leading to the elongated morphology of celiac DCs upon adhesion on fibronectin, confirming the role of this pathway in the observed phenotype. In conclusion, adhesion on fibronectin discriminated CD from the controls’ DCs, revealing a gluten-independent CD-specific cellular phenotype related to DC shape and regulated by RhoA activity.
... The zinc finger domains in the LIM domain of the LASP1 N-terminus can bind to chemokine receptors (CXCR2) and colocalize at the edge of the migrating cells, which plays an important role in the local movement and adhesion of cells. 29 At the adhesion point of the lesion, the C-terminal SH3 domain of LASP1 is involved in binding to zyxin, 30 lipoma preferred partner (LPP), 31 and vasodilator stimulated phosphoprotein (VASP), 32 which regulates cell movement, adhesion, and shape changes. It has been found that LASP1 is mainly located at focal adhesions, 33,34 in podosomes, 35 and at the leading edges of lamellipodia, 36 and is closely related to the adhesion and dynamic actin assembly of cells. ...
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors of the digestive tract in humans. Several studies have indicated that PAK4 is associated with the risk of ESCC and may be a potential druggable kinase for ESCC treatment. However, the underlying mechanism remains largely unknown. The aim of our study is to identify the functional role of PAK4 in ESCC. To determine the expression of PAK4 in ESCC, Western blot analysis and immunohistochemistry were performed, and the results showed that PAK4 is significantly upregulated in ESCC tissues and cell lines compared with normal controls and normal esophageal epithelial cell line. To further investigate the role of PAK4 in ESCC, cell viability assays, anchorage‐independent cell growth assays, wound healing assays, cellular invasion assays, in vivo xenograft mouse models, and metastasis assays were conducted, and the results showed that PAK4 can significantly facilitate ESCC proliferation and metastasis in vitro and in vivo. To determine the potential target of PAK4 in ESCC progression, a pull‐down assay was performed, and the results showed that LASP1 may be a potential target of PAK4. An immunoprecipitation assay and confocal microscopy analysis confirmed that PAK4 can bind to and colocalize with LASP1 in vitro and in cells. Notably, rescue experiments further illustrated the mechanistic network of PAK4/LASP1. Our research reveals the oncogenic roles of PAK4 in ESCC and preliminarily elucidates the mechanistic network of PAK4/LASP1 in ESCC.
... Its reading frame contains 1836 nucleotides encoding 612 amino acids. The expression of this gene was first discovered in human benign and malignant tumors, which may be related to cell migration and proliferation of tumors (Jin et al. 2007), and also plays an important role in cell proliferation and transcription (Grunewald et al. 2009). The results of Zhang et al. suggest that the LPP gene might be a novel candidate for PCOS by 1132 PCOS cases and 1142 controls (Zhang et al. 2012). ...
... LPP can increase the ability of cells to migrate and spread (Jin et al. 2007), and may play a role in the distant metastasis and invasion of tumor cells. In summary, LPP plays an important role in cell migration, proliferation, and transcription (Grunewald et al. 2009). Studies have found that LPP genes affect the occurrence of a variety of tumors, such as multiple myeloma (Li et al. 2018), ovarian cancer (Leung et al. 2018), and lung cancer (Kuriyama et al. 2016). ...
Astrocytoma is the most common neuroepithelial tumor. Genetic factors play an important role in the development and prognosis of astrocytoma. So this study focuses on the impact of LPP and RYR2 genes on the occurrence and prognosis of astrocytoma. Rs12594 and rs16835904 in the RYR2 gene and rs1064607, rs3796283, and rs2378456 in the LPP gene were selected and genotyped using Agena MassARRAY in 365 patients and 379 healthy populations. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined using logistic regression to assess the influence of gene polymorphisms on occurrence of astrocytoma. The association between genotype and survival outcomes was performed by the Kaplan-Meier method, the log-rank test, and the Cox regression analysis. The survival rates of patients receiving gross total resection and postoperative chemotherapy were higher than patients receiving near total resection and subtotal resection and without chemotherapy. In recessive model, the patients with LPP rs2378456 CC genotype increased the risk of astrocytoma (OR = 1.43, 95% CI 1.01–2.02, p = 0.042). Stratified analysis shows that RYR2 rs16835904 TC-TT genotype facilitated the risk of astrocytoma in male (OR = 1.93, 95% CI 1.15–3.24, p = 0.011). Cox regression analysis shows that RYR2 rs12594 AA genotype and AG genotype were associated with OS of astrocytoma (AG genotype: HR = 1.62, 95% CI 1.04–2.53, p = 0.034; AA genotype: HR = 1.70, 95% CI 1.08–2.68, p = 0.021). RYR2 and LPP genes were found to affect the occurrence and prognosis of astrocytoma.
... LPP. EGPA-associated rs9290877 is within LPP, encoding a LIM domain protein 25 , and is associated with asthma, allergy and plasma IgE (Supplementary Table 10, Supplementary Data 1). CHiCP analysis links this variant to BCL6 (Fig. 2b), encoding a transcriptional repressor central to immune, and in particular TH2, regulation; BCL6-deficient mice die of overwhelming eosinophilic inflammation characterised by myocarditis and pulmonary vasculitis 26 . ...
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA. Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder characterised by asthma, eosinophilia and vasculitis. Here, the authors describe a genome-wide association study of EGPA that reveals clinical and genetic differences between subgroups stratified by autoantibody status (ANCA).
... EGPA-associated rs9290877 is within LPP, encoding a LIM domain protein (25), and is associated with asthma, allergy and plasma IgE, (Supplementary Table 11). CHiCP analysis links the SNP to BCL6 (Figure 2B), encoding a transcriptional repressor central to immune, and in particular TH2, regulation; BCL6-deficient mice die of overwhelming eosinophilic inflammation characterized by myocarditis and pulmonary vasculitis (26). ...
Eosinophilic granulomatosis with polyangiitis (EGPA: formerly Churg-Strauss syndrome) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasm antibodies (ANCA) specific for myeloperoxidase (MPO). We performed a genome-wide association study (GWAS) of EGPA, testing 7.5 million genetic variants in 684 cases and 6,838 controls. Case-control analyses were performed for EGPA as a whole, and stratified by ANCA. To increase power, we used a conditional false discovery rate method to leverage findings from GWASs of related phenotypes. In total, 11 variants were associated with EGPA, two specifically with ANCA-negative EGPA, and one (HLA-DQ) with MPO+ANCA EGPA. Many variants were associated with asthma, eosinophilic and immune-mediated diseases and, strikingly, nine were associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia underlies EGPA susceptibility. We demonstrate that EGPA comprises two genetically and clinically distinct syndromes, with ANCA-negative EGPA genetically more similar to asthma. MPO+ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an MHC association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Five identified candidate genes are targets of therapies in development, supporting their exploration in EGPA.
