Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resistance to the BCR-ABL tyrosine kinase inhibitor imatinib poses a pressing challenge in treating chronic myeloid leukemia (CML). This resistance is often caused by point mutations in the ABL kinase domain or by overexpression of LYN. The second-generation BCR-ABL inhibitor INNO-406 is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. We have performed an unbiased chemical proteomics native target profile of INNO-406 in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new INNO-406 targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of INNO-406. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, INNO-406 does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make INNO-406 a valuable component in the drug arsenal against CML.
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PMID:A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. 1989 Mar 74

Collagen fiber assembly affects many physiological processes and is tightly controlled by collagen-binding proteins. However, to what extent membrane-bound versus cell-secreted collagen-binding proteins affect collagen fibrillogenesis is not well understood. In our previous studies, we had demonstrated that the membrane-anchored extracellular domain (ECD) of the collagen receptor discoidin domain receptor 2 (DDR2) inhibits fibrillogenesis of collagen endogenously secreted by the cells. These results led to a novel functional role of the DDR2 ECD. However, since soluble forms of DDR1 and DDR2 containing its ECD are known to naturally exist in the extracellular matrix, in this work we investigated if these soluble DDR ECDs may have a functional role in modulating collagen fibrillogenesis. For this purpose, we created mouse osteoblast cell lines stably secreting DDR1 or DDR2 ECD as soluble proteins. Transmission electron microscopy, fluorescence microscopy, and hydroxyproline assays were used to demonstrate that DDR ECD expression reduced the rate and quantity of collagen deposition and induced significant changes in fiber morphology and matrix mineralization. Collectively, our studies advance our understanding of DDR receptors as powerful regulators of collagen deposition in the ECM and elucidate their multifaceted role in ECM remodeling.
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PMID:Inhibition of collagen fibrillogenesis by cells expressing soluble extracellular domains of DDR1 and DDR2. 1990 Apr 59

The discoidin domain receptors, DDR1 and DDR2, are widely expressed receptor tyrosine kinases that are activated by triple-helical collagen. They control important aspects of cell behavior and are dysregulated in several human diseases. The major DDR2-binding site in collagens I-III is a GVMGFO motif (O is hydroxyproline) that also binds the matricellular protein SPARC. We have determined the crystal structure of the discoidin domain of human DDR2 bound to a triple-helical collagen peptide. The GVMGFO motifs of two collagen chains are recognized by an amphiphilic pocket delimited by a functionally critical tryptophan residue and a buried salt bridge. Collagen binding results in structural changes of DDR2 surface loops that may be linked to the process of receptor activation. A comparison of the GVMGFO-binding sites of DDR2 and SPARC reveals a striking case of convergent evolution in collagen recognition.
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PMID:Crystallographic insight into collagen recognition by discoidin domain receptor 2. 2000 61

Vitiligo is a chronic disease characterized by macules devoid of melanin and identifiable melanocytes. Adhesion of melanocytes to the basement membrane by integrin CCN3 is mediated through collagen IV receptor DDR1. We hypothesize that genetic variants of the DDR1 gene are associated with the occurrence of vitiligo. To test this hypothesis, we genotyped 10 DDR1 tag single-nucleotide polymorphisms (SNPs) in 212 trios composed of an affected child and both parents. Associated markers were then genotyped in 134 independent, unrelated individuals with vitiligo and 134 unrelated controls. Allele T of tag SNP rs4618569 was associated with an increased risk for vitiligo in the family trios (P=0.002, odds ratio (OR)=5.27; 95% confidence interval (CI)=1.59-17.40), whereas allele C of tag SNP rs2267641 was associated with an increased risk for vitiligo in both family-based and case-control populations (P=0.01, OR=3.47; 95% CI=1.22-9.17; P=0.04, OR=6.00; 95% CI=1.73-52.33, respectively). The best evidence for association in the trios was obtained for a haplotype composed of risk alleles of markers rs4618569 and rs2267641 (P=0.0006). There was an age-dependent enrichment of rs4618569 T allele and rs2267641 C allele in early-onset affected individuals. In conclusion, we propose DDR1 as a susceptibility gene for vitiligo, possibly implicating a defective cell adhesion in vitiligo pathogenesis.
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PMID:Genetic variants of the DDR1 gene are associated with vitiligo in two independent Brazilian population samples. 2018 41

We describe a strategy for comprehending signaling pathways that are active in lung cancer cells and that are targeted by dasatinib using chemical proteomics to identify direct interacting proteins combined with immunoaffinity purification of tyrosine-phosphorylated peptides corresponding to activated tyrosine kinases. We identified nearly 40 different kinase targets of dasatinib. These include SRC-family kinase (SFK) members (LYN, SRC, FYN, LCK and YES), nonreceptor tyrosine kinases (FRK, BRK and ACK) and receptor tyrosine kinases (Ephrin receptors, DDR1 and EGFR). Using quantitative phosphoproteomics, we identified peptides corresponding to autophosphorylation sites of these tyrosine kinases that are inhibited in a concentration-dependent manner by dasatinib. Using drug-resistant gatekeeper mutants, we show that SFKs (particularly SRC and FYN), as well as EGFR, are relevant targets for dasatinib action. The combined mass spectrometry-based approach described here provides a system-level view of dasatinib action in cancer cells and suggests both functional targets and a rationale for combinatorial therapeutic strategies.
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PMID:A chemical and phosphoproteomic characterization of dasatinib action in lung cancer. 2019 Jul 65

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm composed of CD34-positive fibroblastic cells. The pathogenesis driving this neoplasm remains unclear, with no recurrent genetic aberrations described to date. Previous reports suggest a role for IGF2 over-expression in the pathogenesis of these tumours, implicated in triggering hypoglycaemia in some patients. The expression profiling of 23 SFTs was investigated using an Affymetrix U133A platform. The transcriptional signature was compared to a set of 34 soft tissue sarcomas spanning seven subtypes. Potential candidate genes were then further investigated for activating mutations or loss of imprinting (LOI). SFT had a distinct expression signature and clustered in a tight genomic cluster, separate from all other sarcoma subtypes. A number of over-expressed receptor tyrosine kinase (RTK) genes were identified in SFT, including DDR1, ERBB2 and FGFR1; however, no mutations were identified by cDNA sequencing. Over-expression of IGF2 was uniformly detected in SFT, regardless of anatomical location, and was related to LOI. In contrast, IGF1 and JUN over-expression was seen in pleural, but not meningeal, locations. SFT shows a distinctive expression signature, with over-expression of DDR1, ERBB2 and FGFR1. Despite of lack of activating mutations in these RTKs, therapy with specific inhibitors targeting these kinases might be considered in advanced/metastatic cases. Our results confirm LOI in several tumours expressing high levels of IGF2, which may explain the observed paraneoplastic hypoglycaemia.
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PMID:IGF2 over-expression in solitary fibrous tumours is independent of anatomical location and is related to loss of imprinting. 2052 23

Discoidin domain receptors (DDRs) are a novel class of receptor tyrosine kinases that bind to several collagens and facilitate cell adhesion. DDR1 is involved in cancer invasion. However, very limited data are available on the aspect of clinical significance of DDR1 expression in cancer. The aim of this study was to investigate prognostic impact of DDR1 expression in non-small cell lung carcinoma (NSCLC). Tumor tissues from 171 NSCLC, including 86 squamous cell carcinomas, 69 adenocarcinomas, and 16 pure bronchioloalveolar carcinomas (BAC), were analyzed for expression of DDR1 using immunohistochemical staining. In addition, two lung adenocarcinoma cell lines (A549, H358) were transfected with two isoforms of DDR1, DDR1a and DDR1b, and then migration and invasion assays were carried out. DDR1 was expressed in 6 of 16 BAC (38%) and 95 of 155 invasive NSCLC (61%, p=0.065). DDR1 up-regulation tend to be more frequently observed in invasive adenocarcinoma (64%) compared to DDR1 expression in BAC (38%) (p=0.056). In invasive NSCLC, DDR1 expression was significantly correlated with lymph node metastasis (p=0.001). Overexpression of DDR1 in lung cancer cells resulted in a significant increase of cell motility and invasiveness (p<0.001) and the interaction of DDR1 with collagen facilitates the invasiveness of NSCLC cells. DDR1 overexpression produced an activation of MMP-9 in H358 cells. In conclusion, these findings indicate that up-regulation of DDR1 may contribute to the progression and poor prognosis of NSCLC and this effect may be associated with increased invasiveness.
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PMID:Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung carcinomas. 2059 15

CD9 is a member of the tetraspanin family and is widely expressed in the plasma membrane of several cell types as well as malignant cells. CD9 associates with a number of transmembrane proteins, which facilitates biological processes, including cell signaling, adhesion, migration and proliferation. DDR1 is activated by native type IV collagen and overexpressed in human breast cancer. Type IV collagen is the main component of basement membranes, and may interact with cell surface biomolecules, promoting adhesion and motility. However, the role of DDR1 and type IV collagen in the regulation of CD9-cell surface levels and migration in breast cancer cells has not been studied in detail. We demonstrate here that native type IV collagen induces a transient increase of CD9-cell surface levels through a DDR1-dependent pathway in MDA-MB-231 breast cancer cells, as revealed by flow cytometry and Western blotting using specific antibodies that recognize CD9. In contrast, type IV collagen does not induce any increase of CD9-cell surface levels in the mammary non-tumorigenic epithelial cells MCF10A and MCF12A. Transient increase of CD9-cell surface levels is coupled with clathrin-mediated endocytosis and it is dependent of DDR1 expression. In addition, type IV collagen induces cell migration through a DDR1 and CD9-dependent pathway. In summary, our data demonstrate, for the first time, that native type IV collagen induces a transient increase of CD9-cell surface levels and cell migration through a DDR1 and CD9-dependent pathway in MDA-MB-231 breast cancer cells.
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PMID:Native type IV collagen induces cell migration through a CD9 and DDR1-dependent pathway in MDA-MB-231 breast cancer cells. 2070 24

Discoidin domain receptor (DDR)1 is an extracellular matrix (ECM)-sensing receptor tyrosine kinase, which is activated by collagen and expressed in bronchial epithelium. DDR1 is responsible for maintaining the normal structure of skin and kidney epithelia and we hypothesised that DDR1 plays a regulatory role in bronchial epithelial integrity by transducing signals from the airway ECM. Effects of DDR1 depletion were studied using RNA interference in primary human bronchial epithelial cells (HBECs) and BEAS-2B cells. The effects of overexpression of DDR1a and DDR1b in BEAS-2B cells were studied using a plasmid vector. We measured the effects on epithelial repair using a scratch wounding model, and levels of matrix metalloproteinases (MMPs) by gelatin zymography (MMP-2 and -9) and ELISA (MMP-7). We showed that knockdown of DDR1 slowed epithelial repair by 50%, which was associated with a reduction in levels of MMP-7, whilst DDR1 overexpression enhanced epithelial repair. DDR1 knockdown reduced proliferation of HBECs, but had no significant effect on adhesion to collagen I or other matrix substrates. These data suggest that ECM signalling via DDR1 regulates aspects of bronchial epithelial repair, integrity and MMP expression in the airways.
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PMID:Discoidin domain receptor 1 regulates bronchial epithelial repair and matrix metalloproteinase production. 2088 41

The discoidin domain receptors, DDR1 and DDR2 are cell surface receptor tyrosine kinases that are activated by triple-helical collagen. While normal DDR signalling regulates fundamental cellular processes, aberrant DDR signalling is associated with several human diseases. We previously identified GVMGFO (O is hydroxyproline) as a major DDR2 binding site in collagens I-III, and located two additional DDR2 binding sites in collagen II. Here we extend these studies to the homologous DDR1 and the identification of DDR binding sites on collagen III. Using sets of overlapping triple-helical peptides, the Collagen II and Collagen III Toolkits, we located several DDR2 binding sites on both collagens. The interaction of DDR1 with Toolkit peptides was more restricted, with DDR1 mainly binding to peptides containing the GVMGFO motif. Triple-helical peptides containing the GVMGFO motif induced DDR1 transmembrane signalling, and DDR1 binding and receptor activation occurred with the same amino acid requirements as previously defined for DDR2. While both DDRs exhibit the same specificity for binding the GVMGFO motif, which is present only in fibrillar collagens, the two receptors display distinct preferences for certain non-fibrillar collagens, with the basement membrane collagen IV being exclusively recognised by DDR1. Based on our recent crystal structure of a DDR2-collagen complex, we designed mutations to identify the molecular determinants for DDR1 binding to collagen IV. By replacing five amino acids in DDR2 with the corresponding DDR1 residues we were able to create a DDR2 construct that could function as a collagen IV receptor.
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PMID:Collagen binding specificity of the discoidin domain receptors: binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1. 2104 84


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