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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ph chromosome was the first specific karyotype abnormality associated with a particular neoplastic disease in humans. For many years it was suspected that chromosome abnormalities might cause cancer by alteration of specific genes or their expression. Significant recent developments in our understanding of the molecular consequences of the Ph translocation strengthen that assumption. The Ph translocation generates a hybrid gene consisting of 5' regulatory, promotor, and exon sequences of the bcr gene on chromosome 22 fused to 3' exons and polyadenylation/termination sequences of the ABL proto-oncogene from chromosome 9. It is well established that fusion of bcr and abl genes plays a crucial role in the pathogenesis of CML and ALL. Molecular methods can therefore be used as diagnostic tools to detect the Ph chromosome. Presently, the model of oncogenesis provided by our knowledge of how the abl proto-oncogene becomes activated as a result of the Ph translocation is one of the clearest models of oncogene activation. Despite the progress made, many areas remain to be explored. One important question is, how the hybrid protein is involved in leukemia. Research aimed at investigating the normal function of abl and bcr may be important in efforts to understand their abnormal functioning in leukemia and to increase our understanding of the disease.
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PMID:Molecular insights into the Philadelphia translocation. 205 Jun

A number of protooncogenes have been implicated in human tumorigenesis. The ABL oncogene is consistently rearranged and activated as a consequence of the translocation t(9;22) that gives rise to the Philadelphia chromosome in chronic myeloid leukemia and in some cases of acute lymphoblastic leukemia. Here we describe rearrangement of ABL in a different type of malignancy. The glioblastoma cell line A172 lacks germline alleles of ABL. A recombination event, presumably followed by a duplication, has created two ABL alleles in which exon 11 is joined to chromosome 16 sequences. Although the main body of ABL exons was still present, two considerably shortened ABL mRNAs of 3.8 and 2.8 kilobases were detected; the 3.8-kilobase mRNA hybridized exclusively to an exon IB probe. Neither mRNA hybridized to an ABL probe encompassing part of the tyrosine kinase domain. Thus, the cell line A172 is able to survive in the absence of a functional ABL gene product, indicating that the role of ABL is unlikely to be "housekeeping."
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PMID:Rearrangement of the human ABL oncogene in a glioblastoma. 233 39

The long terminal repeat (LTR) of the pre-B cell tropic Abelson murine leukemia virus (A-MuLV) was replaced with the LTR of the erythrotropic Friend MuLV or with the LTR of the erythropic/fibrotropic Harvey murine sarcoma virus (Ha-MuSV) to generate the viruses F-ABL and H-ABL, respectively. The parental A-MuLV and the recombinant viruses induced pre-B cell lymphomas in susceptible mice with similar frequencies. Recombinant virus-induced tumor DNAs were analysed by nucleic acid hybridization and were shown to contain the appropriate recombinant provirus. F-ABL was 100-1000 fold less efficient than A-MuLV or H-ABL in the in vitro transformation of primary bone marrow cells, as detected by lymphoid colony formation in agarose. To compare the level of transcription initiated from the different viral LTRs, we investigated the ability of the U3 region of these retroviral LTRs to promote transcription in a battery of cell lines using the chloramphenicol acetyl-transferase (CAT) assay, and with some exceptions we found the following hierarchy of activities: Ha-MusSV greater than or equal to M-MuLV greater than A-MuLV greater than F-MuLV, regardless of the cell line transfected. These results indicate that the LTR is not a determinant of the pre-B cell disease specificity of A-MuLV, and suggest that this specificity resides in the v-abl oncogene. Also, our results suggest that a threshold amount of the v-abl protein product is necessary for in vitro transformation, and this level of expression may be different from the level selected during in vivo tumorigenesis.
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PMID:Substitution of the LTR of Abelson murine leukemia virus does not alter the cell type of virally induced tumors. 283 88

The human adenovirus type 12 (H12) E1A region encodes two early proteins of 266 amino acid residues (266R) and 235R whilst the H12 E1B promoter directs the synthesis of two major proteins of 163R and 482R. To determine the functions of E1A and E1B in lytic infection and oncogenic transformation we have isolated and characterized a series of H12 E1 mutants. Mutant H12 hr 700 contains a point mutation in exon 1 that alters a single amino acid common to both the 266 and 235R proteins. This mutant synthesized reduced levels of E1 and structural proteins at delayed times in HEK cells, transformed BRK cells, and induced tumors in newborn rats at reduced efficiency compared to wild-type virus. The mutation in H12 in 600 truncates the 266R protein in its unique sequences but this mutant synthesized the 235R, E1B, and structural proteins at delayed times in HEK cells. H12 in 600 was nontransforming but induced rare tumors in newborn rats. A third E1A mutant H12 in 601 synthesized no E1A proteins, reduced levels of E1B and structural proteins at delayed times in lytic infections, and was not a transforming or oncogenic virus. Three E1B mutants were studied in detail. Both H12 hr 703 and H12 in 602 encode N-terminal truncated 482R proteins whereas H12 del 620 encodes an in-frame internally deleted 482R protein. All three synthesized reduced amounts of E1A proteins and the E1B 163R protein, identifying a regulatory function for the 482R protein. None of the E1B mutants could transform and only H12 del 620 could induce rare tumors in newborn rats. These results show that H12 oncogenesis requires the coordinated expression of the E1 proteins.
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PMID:Host range mutants of adenovirus type 12 E1 defective for lytic infection, transformation, and oncogenicity. 296 53

Cytokines that interact with receptors of the hematopoietin super-family have recently been reported to stimulate receptor-associated JAK tyrosine kinases, including PRL activation of JAK2. Unlike other tyrosine kinases, none of the JAK kinases has thus far been implicated in oncogenesis, and their involvement in growth signaling has not been established. Using the PRL-dependent pre-T-cell line Nb2, the present study provided a link between bivalent dimerization of a hematopoietin receptor and activation of its associated JAK kinase, and demonstrated a strong positive correlation between the mitogenic potency of a series of bivalent anti-PRL receptor antibodies and the degree of induced tyrosine phosphorylation of JAK2. Antibody bivalency was required for JAK2 phosphorylation. Monovalent anti-PRL receptor Fab fragments alone were inactive, but their activity could be partially restored by cross-linking with bivalent anti-Fab antibodies. Additional evidence for antibody-induced receptor dimerization was provided by a bell-shaped dose-response curve for the most potent receptor agonist, monoclonal antibody T6. This phenomenon is typically seen at pharmacological concentrations of bivalent ligands, when bound ligand molecules fail to adjoin a second receptor due to occupancy. The present study provided functional support for a model of PRL receptor triggering by ligand-induced receptor homodimerization and subsequent activation of the associated tyrosine kinase JAK2.
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PMID:JAK2 activation and cell proliferation induced by antibody-mediated prolactin receptor dimerization. 792 91

BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph1)-positive human leukemias. Sequences within the first exon of BCR are required to activate the transforming potential of BCR-ABL. The SH2/SH3 domain-containing GRB-2 protein links tyrosine kinases to Ras signaling. We demonstrate that BCR-ABL exists in a complex with GRB-2 in vivo. Binding of GRB-2 to BCR-ABL is mediated by the direct interaction of the GRB-2 SH2 domain with a phosphorylated tyrosine, Y177, within the BCR first exon. The BCR-ABL-GRB-2 interaction is required for activation of the Ras signaling pathway. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation. The BCR-ABL (Y177F) mutant is unable to transform primary bone marrow cultures and is impaired in its ability to transform Rat1 fibroblasts. These findings implicate activation of Ras function as an important component in BCR-ABL-mediated transformation and demonstrate that GRB-2 not only functions in normal development and mitogenesis but also plays a role in oncogenesis.
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PMID:BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. 840 96

The TAL-1 gene specifies for a basic domain-helix-loop-helix protein, which is involved in the control of normal hematopoiesis. In human pathology, the TAL-1 gene product is expressed in a high percentage of T-cell acute lymphoblastic leukemias in the pediatric age range; however, it has not been established whether the expression has a causal role in oncogenesis. In this report, we describe the phenotype of mouse transgenic lines obtained by inducing tal-1 protein expression in lymphoid tissues using the LCK promoter. The survival rate of tal-1 transgenic animals was much lower as compared with control mice. Histopathological analysis revealed lymphomas of T-cell type, often comprising a minor B-cell component. Some mice showed marked splenic lymphocyte depletion. Primary lymphocyte cultures showed partial independence from exogenous growth stimuli and increased resistance to low-serum apoptosis. To further unravel the tal-1 oncogenic potential, a strain of tal-1 transgenic mice was crossbred with p53-/- mice; the survival rate in these animals was reduced by more than one-half when compared with that of tal-1 mice, and histopathological analysis revealed exclusively T-cell lymphomas. These data indicate that TAL-1, expressed in T cells, is per se a potent oncogene, which may exert a key leukemogenetic role in the majority of T-cell acute lymphoblastic leukemias.
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PMID:T-cell-directed TAL-1 expression induces T-cell malignancies in transgenic mice. 891 42

Focal adhesion kinase (pp125FAK, FAK) is a structurally unique nonreceptor tyrosine kinase that is localized in the focal adhesion plaques. Activation or modulation of this kinase has been associated with several signaling pathways including integrin mediated processes, mitogenic stimulation by neuropeptides and platelet-derived growth factor as well as oncogene-mediated transformation. These observations suggest that FAK may play a potential role in tumorigenesis and/or tumor invasiveness. Since the phosphotyrosine content of FAK has been implicated in both the activation of its catalytic activity and the recruitment of SH2 containing proteins, the expression, phosphorylation status and enzymatic activity of FAK was examined in a number of human tumor and normal cell lines. FAK was detectable in all cell lines with fairly consistent levels of expression. In contrast, constitutive tyrosine phosphorylation of FAK was quite variable among both normal and tumor cell lines. A direct correlation (correlation coefficient = 0.94) was observed between FAK activity and phosphotyrosine content. Within the cell lines examined, colon carcinomas exhibited marked elevation in FAK tyrosine kinase activity and phosphotyrosine content. These data suggest that colon carcinomas have elevated FAK activity in comparison to other tumor types and provide further support that the catalytic activity of FAK is enhanced by its phosphotyrosine content.
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PMID:Correlations between the expression, phosphotyrosine content and enzymatic activity of focal adhesion kinase, pp125FAK, in tumor and nontransformed cells. 893 37

Allelic loss of chromsome 19q occurs frequently in malignant gliomas, suggesting the presence of a chromosome 19q glioma tumor suppressor gene. Deletion mapping studies have delineated a 3.5 Mb candidate region between D19S219 and HRC. Cloned sequences from the proximal 425 kb of this interval, however, have not shown tumor-specific alterations. To refine the location of the tumor suppressor gene further, we conducted loss of heterozygosity studies on 191 malignant gliomas using nine PCR-based polymorphisms. These included the previously identified and physically mapped markers D19S219, DM, D19S112, HRC and the recently physically mapped polymorphisms at D19S412, STD, D19S596 and GYS. In addition, we isolated a novel microsatellite polymorphism that maps 400 kb telomeric to D19S112. Oligodendroglial tumors showed frequent loss of heterozygosity in all grades, and typically displayed allelic loss at all studied markers. Astrocytomas, however, showed frequent loss primarily in anaplastic astrocytomas and displayed deletion breakpoints within the candidate region. Deletion mapping revealed a minimal region of overlap between D19S412 and STD, a distance of 900 kb. These data suggest that the D19S412-STD interval represents the most likely location for a chromsome 19q glioma tumor suppressor gene involved in astrocytoma, and perhaps oligodendroglioma, tumorigenesis.
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PMID:Refined deletion mapping of the chromosome 19q glioma tumor suppressor gene to the D19S412-STD interval. 895 92

Integrins can trigger signals by activation of cytoplasmic tyrosine kinases, including pp125FAK. Preliminary evidence suggests that serine/threonine kinases such as ERKs may also be activated via integrins. Thus, there seems to be at least partial overlap between RTK signaling pathways and integrin signaling. In tumor cells, ectopic expression or over-expression of certain integrins such as alpha 5/beta 1 can result in reduced tumorigenesis. Presumably the effects of integrins on tumor growth are mediated by the integrin signaling pathway(s) involving FAK and ERKs. However, the precise mechanisms involved have not yet been elucidated.
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PMID:Integrin signals and tumor growth control. 898 69


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