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)

Protein tyrosine kinase transmembrane receptors trigger signal transduction cascades upon ligand binding, resulting in cellular proliferation, differentiation, differentiation inhibition or apoptosis depending upon the cell target. The ETK2/TYRO3 receptor is a tyrosine kinase expressed in embryonic stem cells, brain and testis that has recently been cloned by several groups. Analysis of cDNA clones isolated from several tissues shows 2 isoforms of the Etk2/tyro3 gene product that result from usage of alternative exons near the 5' end of the gene. In addition, our data suggest that a third alternative exon is positioned between these two alternative exons. This novel exon encodes yet another isoform that predicts a unique amino-terminal protein sequence. The alternative exons (exons 2A, 2B and 2C), predict three isoforms with different initiation codons, signal sequences and lengths. The existence of these multiple isoforms may be important for protein processing, translocation, or function.
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PMID:Identification of alternative exons, including a novel exon, in the tyrosine kinase receptor gene Etk2/tyro3 that explain differences in 5' cDNA sequences. 778 69

Partial cDNAs of the human TYRO3 gene, encoding a putative receptor tyrosine kinase, and its processed pseudogene (TYRO3P) were cloned from human teratocarcinoma cell, bone marrow and melanocyte cDNA libraries. The tyrosine kinase homologous domains of TYRO3 and TYRO3P were sequenced and compared with each other and with the mouse TYRO3 gene. Abundant levels of the 4.2-kb TYRO3 mRNA were detected in human brain, and lower levels in other human tissues. TYRO3 and TYRO3P were both assigned to human chromosome 15q14-q25 by analysis of DNAs from somatic cell hybrids.
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PMID:The human TYRO3 gene and pseudogene are located in chromosome 15q14-q25. 826 88

Diffuse astrocytoma WHO grade II is a well-differentiated, slowly growing tumor that has an inherent tendency to progress to anaplastic astrocytoma (WHO grade III) and, eventually, to glioblastoma (WHO grade IV). Little is known about its molecular basis, except for p53 mutations that are found in >60% of cases. In a search for additional genetic alterations, we carried out gene expression profiling of 11 diffuse astrocytomas using cDNA expression arrays. Expression of six genes (TIMP3, c-myc, EGFR, DR-nm23, nm23-H4, and GDNPF) was detected in 64-100% of diffuse astrocytomas, but not in nontumorous brain tissue. Seven genes (AAD14, SPARC, LRP, PDGFR-alpha, 60S ribosomal protein L5, PTN, and hBAP) were found to be up-regulated more than 2-fold in 20-60% of cases, whereas 11 genes (IFI 9-27, protein kinase CLK, TDGF1, BIN1, GAB1, TYRO3, LDH-A, adducin 3, GUK1, CDC10, and KRT8) were down-regulated to less than 50% of normal levels in 64-100% of cases. Semiquantitative conventional reverse transcription-PCR was performed for 11 genes, 9 of which showed an expression profile similar to that obtained with cDNA expression arrays. Immunohistochemical staining for SPARC showed cytoplasmic immunoreactivity of neoplastic cells in all diffuse astrocytomas analyzed. These results indicate significant changes in gene expression in diffuse astrocytomas, but it remains to be shown which of these are causally related to the transformation of glial cells.
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PMID:Gene expression profiling of low-grade diffuse astrocytomas by cDNA arrays. 1115 82

The T-box (Tbx) genes encode a family of transcription factors required for development of vertebrate embryos. In an attempt to discover human orthologues of the zebrafish (Danio rerio) tbx6 and tbx16/spadetail genes, we found that the most similar human (Homo sapiens) gene is the orthologue of mouse (Mus musculus) Mga (MAX gene associated). We have identified the zebrafish orthologue of Mga using analyses of sequence similarity and the orthologies of syntenic genes. Zebrafish mga maps close to dtk (developmental receptor tyrosine kinase), the orthologue of human TYRO3 (TYRO3 protein tyrosine kinase). Like its human and mouse orthologues, zebrafish mga lacks the three conserved introns within the T-box coding sequences that are characteristic of the vertebrate T-box gene family. This suggests that these genes are derived from an ancient reverse transcription event. The human genome does not appear to possess orthologues of zebrafish tbx6 or tbx16/spadetail.
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PMID:The evolutionary relationships of zebrafish genes tbx6, tbx16/spadetail and mga. 1290 7

Recent studies have revealed that the TAM receptor protein tyrosine kinases--TYRO3, AXL and MER--have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.
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PMID:Immunobiology of the TAM receptors. 1842 5

Complex signaling pathways operate in human embryonic stem cells (hESCs) and are coordinated to maintain self-renewal and stem cell characteristics in them. Protein tyrosine kinases (PTKs) participate in diverse signaling pathways in various types of cells. Because of their functions as key molecules in various cellular processes, PTKs are anticipated to have important roles also in hESCs. In this study, we investigated the roles of PTKs in undifferentiated and differentiated hESCs. To establish comprehensive PTK expression profiles in hESCs, we performed reverse transcriptase PCR using degenerate primers according to the conserved catalytic PTK motifs in both undifferentiated and differentiated hESCs. Here, we identified 42 different kinases in two hESC lines, including 5 non-receptor tyrosine kinases (RTKs), 24 RTKs, and 13 dual and other kinases, and compared the protein kinase expression profiles of hESCs and retinoic acid-treated hESCs. Significantly, up- and downregulated kinases in undifferentiated hESCs were confirmed by real-time PCR and western blotting. MAP3K3, ERBB2, FGFR4, and EPHB2 were predominantly upregulated, while CSF1R, TYRO3, SRC, and GSK3A were consistently downregulated in two hESC lines. Western blot analysis showed that the transcriptional levels of these kinases were consistent with the translational levels. The obstruction of upregulated kinases' activities using specific inhibitors disturbed the undifferentiated status and induced the differentiation of hESCs. Our results support the dynamic expression of PTKs during hESC maintenance and suggest that specific PTKs that are consistently up- and downregulated play important roles in the maintenance of stemness and the direction of differentiation of hESCs.
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PMID:Expression profiles of protein tyrosine kinase genes in human embryonic stem cells. 1858 72

Interferons (IFNs) were discovered as antiviral agents 50 years ago, and enormous progress has been made since then. Nowadays, IFNs (specifically type I IFNs), have been ascribed as the cytokines that bridge the innate and adaptive immunity soon after the recognition of pathogen-associated molecular patterns (PAMPs) by the infected host. Notably, a unifying mechanism for type I IFN production has been established upon innate immune detection. Thus, TLR 3, 4, 7 and 9 associate endosomal recognition of PAMPs to type I IFN responses, a mechanism that has been shown in plasmacytoid dendritic cells to be dependent on the PI3K/mTOR/S6K pathway. It is worth noting that pathogen recognition triggers a fine-tuned controlled program that not only includes the production of antiviral (IFN) and pro-inflammatory cytokines to initiate the antiviral response but also signals the cessation of the response through the induction of suppressors of cytokine signaling (SOCS). SOCS in turn is under tight regulation of the TAM receptors (protein tyrosine kinase receptors TYRO3, AXL and MER), and activation of which thereby protects the host from the threats of autoimmune diseases.
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PMID:Interferons: signaling, antiviral and viral evasion. 1905 36

Mice lacking TYRO3, AXL and MER (TAM) receptor tyrosine kinases (RTKs) are male sterile. The mechanism of TAM RTKs in regulating male fertility remains unknown. In this study, we analyzed in more detail the testicular phenotype of TAM triple mutant (TAM(-/-)) mice with an effort to understand the mechanism. We demonstrate that the three TAM RTKs cooperatively regulate male fertility, and MER appears to be more important than AXL and TYRO3. TAM(-/-) testes showed a progressive loss of germ cells from elongated spermatids to spermatogonia. Young adult TAM(-/-) mice exhibited oligo-astheno-teratozoospermia and various morphological malformations of sperm cells. As the mice aged, the germ cells were eventually depleted from the seminiferous tubules. Furthermore, we found that TAM(-/-) Sertoli cells have an impaired phagocytic activity and a large number of differentially expressed genes compared to wild-type controls. By contrast, the function of Leydig cells was not apparently affected by the mutation of TAM RTKs. Therefore, we conclude that the suboptimal function of Sertoli cells leads to the impaired spermatogenesis in TAM(-/-) mice. The results provide novel insight into the mechanism of TAM RTKs in regulating male fertility.
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PMID:Functions of TAM RTKs in regulating spermatogenesis and male fertility in mice. 1960 23

Malignant melanoma is the most aggressive form of cutaneous carcinoma, accounting for 75% of all deaths caused by skin cancers. Microphthalmia-associated transcription factor (MITF) is a master gene regulating melanocyte development and functions as a "lineage addiction" oncogene in malignant melanoma. We have identified the receptor protein tyrosine kinase TYRO3 as an upstream regulator of MITF expression by a genome-wide gain-of-function cDNA screen and show that TYRO3 induces MITF-M expression in a SOX10-dependent manner in melanoma cells. Expression of TYRO3 is significantly elevated in human primary melanoma tissue samples and melanoma cell lines and correlates with MITF-M mRNA levels. TYRO3 overexpression bypasses BRAF(V600E)-induced senescence in primary melanocytes, inducing transformation of non-tumorigenic cell lines. Furthermore, TYRO3 knockdown represses cellular proliferation and colony formation in melanoma cells, and sensitizes them to chemotherapeutic agent-induced apoptosis; TYRO3 knockdown in melanoma cells also inhibits tumorigenesis in vivo. Taken together, these data indicate that TYRO3 may serve as a target for the development of therapeutic agents for melanoma.
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PMID:A genomic screen identifies TYRO3 as a MITF regulator in melanoma. 1980 17

Carotid atherosclerosis (CA) is one of the most common causes of stroke, and recent studies suggest that pathways initiated by the interaction of the plasma vitamin K-dependent protein GAS6 with the tyrosine kinase receptors TYRO3, AXL and MERTK (TAM) may have a relevant role in atherogenesis. Furthermore, our previous studies indicated an association between GAS6 and stroke. The aim of this study was to analyse the genetic association between SNPs and haplotypes in GAS6-TAM genes and CA. We performed a case-control study with 233 CA patients confirmed by nuclear magnetic resonance angiography and 202 patients who suffered from cardioembolic (non atherogenic) stroke. For all included subjects information on established risk factors was available. Genotyping of 16 selected tagSNPs was performed by real-time PCR, using either FRET or TaqMan probes. Adjusted logistic regression (LR) analyses indicated that rs2289743 in TYRO3 and rs869016 in MERTK were associated to CA, decreasing its risk (OR [95%CI]=0.39 [0.16-0.94] and OR [95%CI]=0.31 [0.14-0.69], respectively). Linkage disequilibrium results were consistent with the haplotype blocks described in HapMap and adjusted LR analyses revealed that the haplotype ACAA in MERTK , containing the minor allele of the associated SNP, was also associated to CA. No association was observed with GAS6 and AXL variants, which suggests that CA is not the mechanism underlying the reported association between GAS6 and stroke. The association between TYRO3 and MERTK variants and carotid atherosclerosis found in this study reinforces a physiological role of the GAS6-TAM pathway in atherogenesis.
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PMID:Association study between polymorphims in GAS6-TAM genes and carotid atherosclerosis. 2066 4


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