Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations with permanent activation of the stem cell factor receptor KIT have been identified as one potential cause for canine cutaneous mast cell tumours (MCTs). The exact changes in global gene expression patterns associated with permanent activation of KIT in these tumours are unknown. The present study compares, by the use of two dimensional difference gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, the proteomes of canine MCTs, with and without KIT exon 11 tandem duplication. Fifteen differentially expressed proteins were identified in mutated MCTs. These are mainly involved in cytoskeleton structure and cell motility (ACTR2, ACTB and CAPPA1), cell signalling (ARHGDIA) and lipid metabolism (ALOX15 and ACSBG4), or are serum proteins. The results therefore support the notion that KIT mutation is associated with changes in the proteome of affected cells with a major effect on the composition of the cytoskeletal proteome and cell motility proteins. No overlaps were identified when the results were compared with a recent study on the proteomic differences between low- and high-grade tumours, suggesting that KIT-mutated tumours may be regarded as a separate entity of high-grade tumours with potential relevance to therapeutic strategies.
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PMID:Tandem duplication of KIT exon 11 influences the proteome of canine mast cell tumours. 2293 87

The involvement of macroautophagy/autophagy proteins in B-cell receptor (BCR) trafficking, although suspected, is not well understood. We show that ATG5 (autophagy related 5) contributes to BCR polarization after stimulation and internalization into LAMP1 (lysosomal-associated membrane protein 1)+ and major histocompatibility complex class II (MHC-II)+ compartments. BCR polarization is crucial in the context of immobilized antigen processing. Moreover, antigen presentation to cognate T cells is decreased in the absence of ATG5 when the model antigen OVAL/ovalbumin is provided in an immobilized form in contrast to the normal presentation of soluble OVAL. We further show that ATG5 is required for centrosome polarization and actin nucleation in the immune synapse area. This event is accompanied by an increased interaction between ATG16L1 (autophagy related 16-like 1 [S. cerevisiae]) and the microtubule-organizing center-associated protein PCM1 (pericentriolar material 1). In the human B cell line BJAB, PCM1 is required for BCR polarization after stimulation. We thus propose that the ATG12 (autophagy related 12)-ATG5-ATG16L1 complex under BCR stimulation allows its interaction with PCM1 and consequently facilitates centrosome relocalization to the immune synapse, optimizing the presentation of particulate antigens. Abbreviations: ACTB: actin beta; ACTR2/3: ARP2/3 actin-related protein 2/3; APC: antigen-presenting cells; ATG: autophagy-related; BCR: B cell receptor; BECN1/Beclin 1: beclin 1, autophagy related; CDC42: cell division cycle 42; Cr2: complement receptor 2; CSFE: carboxyfluorescein succinimidyl ester; DAPI: 4',6-diamidino-2-phenylindole dihydrochloride; EEA1: early endosome antigen 1; ELISA: enzyme-linked immunosorbent assay; FITC: fluorescein isothyocyanate; GC: germinal center; GJA1/CX3: gap junction protein, alpha 1; Ig: immunoglobulin; LAMP1: lysosomal-associated membrane protein 1; LAP: LC3-associated phagocytosis; LM: littermate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen activated protein kinase; MHC-II: major histocompatibility complex class II; MIIC: MHC class II compartment; OVAL: ovalbumin; PBS: phosphate-buffered saline; PCM1: pericentriolar material 1; PtdIns3K: phosphatidylinositol 3-kinase; PTPRC/CD45RB/B220; Protein tyrosine phosphatase, receptor type, C; SYK: spleen tyrosine kinase; TBS: Tris-buffered saline; TCR: T cell receptor; ULK1: unc-51 like kinase 1.
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PMID:ATG5 is required for B cell polarization and presentation of particulate antigens. 3019 44

Extracellular fragments derived from plasma membrane receptors can play relevant roles in the development/progression of tumor pathologies, thereby offering novel diagnostic or therapeutic opportunities. The truncated variant of somatostatin receptor subtype-5, SST5TMD4, is an aberrantly spliced receptor with 4 transmembrane domains, highly overexpressed in several tumor types, whose C-terminal tail is exposed towards the extracellular matrix, and could therefore be the substrate for proteolytic enzymes. In silico analysis implemented herein predicted 2 possible cleavage sites for metalloproteases MMP2, 9, 14, and 16 in its sequence, which could generate 3 releasable peptides. Of note, expression of those MMPs was directly correlated with SST5TMD4 in several cancer-derived cell lines (ie neuroendocrine tumors and prostate, breast, and liver cancers). Moreover, incubation with SST5TMD4-derived peptides enhanced malignancy features in all cancer cell types tested (ie proliferation, migration, etc.) and blunted the antiproliferative response to somatostatin in QGP-1 cells, acting probably through PI3K/AKT and/or MEK/ERK signaling pathways and the modulation of key cancer-associated genes (eg MMPs, MKI67, ACTR2/3, CD24/44). These results suggest that SST5TMD4-derived peptides could contribute to the strong oncogenic role of SST5TMD4 observed in multiple tumor pathologies, and, therefore, represent potential candidates to identify novel diagnostic, prognostic, or therapeutic targets in cancer.
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PMID:Peptides derived from the extracellular domain of the somatostatin receptor splicing variant SST5TMD4 increase malignancy in multiple cancer cell types. 3090 41