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Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. Nature reviews. The Abelson ABL family of nonreceptor tyrosine kinases, ABL1 and ABL2, transduces diverse extracellular signals to protein networks that control proliferation, survival, migration, and invasion. ABL1 was first identified as an oncogene required for the development of leukemias initiated by retroviruses or chromosome translocations. The demonstration that small molecule ABL kinase inhibitors effectively treat chronic myeloid leukemia opened the door to the era of targeted cancer therapies. Recent reports have uncovered roles for ABL kinases in solid tumors. Enhanced ABL expression and activation in some solid tumors, together with altered cell polarity, invasion or growth induced by activated ABL kinases, suggest that drugs targeting these kinases may have utility in treating selected solid tumors. Tyrosine kinase signaling networks are required for the regulation of multiple cellular processes including growth, survival, invasion and angiogenesis during tumor initiation and progression. Drug discovery efforts in the past two decades have focused on developing tyrosine kinase inhibitors TKIs for cancer therapy. ABL1 was first discovered over 30 years ago as the oncogene in the Abelson murine leukemia virus 1 and later identified as an oncogene associated with chromosome translocations in human leukemias 2. These ABL1 fusion genes encode constitutively activated forms of the ABL1 tyrosine kinase required for cellular transformation. In recent years, activation of ABL1 and ABL2 has been detected in solid tumors, including breast, colon, lung, and kidney carcinoma, as well as melanoma 7 - Here we compare the modes of ABL family kinase activation in leukemias and solid tumors. Further, we dissect the role of the ABL kinases in the regulation of cellular processes critical for the progression of solid tumors including cell polarity, invasion, proliferation and survival. Several FDA-approved drugs targeting ABL kinases including imatinib and dasatinib have been tested for the treatment of solid tumors with mixed effectiveness; potentially due to the complexity of signaling pathways activated in solid tumors, the emergence of therapy resistance, and the fact these inhibitors have multiple cellular targets. Thus, these results highlight the necessity both to develop ABL kinase inhibitors with greater specificity and to identify biomarkers for patient stratification. The Abl1 knockout mice exhibit splenic and thymic atrophy, reduced numbers of B and T cells, cardiac abnormalities, and osteoporosis linked to defective osteoblast proliferation and premature senescence 22 - In contrast, Abl2 Arg knockout mice are viable and exhibit neuronal defects that include age-related dendrite destabilization and regression 27 , ABL1 and ABL2 function redundantly in some cellular contexts, but also have unique roles, owing to distinct and conserved sequences and structural domains Fig. The carboxy C -terminus of both ABL kinases contains a conserved filamentous F actin-binding domain 29 , 30 and reviewed in 6 Fig. In contrast, ABL2, which lacks the NLS motifs, localizes primarily to the cytoplasm and preferentially accumulates at F-actin-rich sites in the cell periphery, focal adhesions, adherens junctions, invadopodia and phagocytic cups 31 - Multiple isoforms of ABL1 and ABL2 have been detected; alternative splicing of the first exons results in isoforms with distinct N-terminal sequences Fig. The 1b isoforms of both ABL kinases contain an N-terminal glycine that is myristoylated, while the 1a variants lack this site and the corresponding modification. Schematic representation of the modular domains of the ABL kinases. Alternative splicing of ABL1 and ABL2 produces several isoforms, including 1a isoforms solid line and the 1b isoforms jagged line ; the later are targeted for N-terminal myristoylation Representation of auto-inhibited closed and active open ABL kinases to depict the role of intramolecular interactions in the regulation of ABL kinase activity. The myristoylated residue in the N-terminus of the 1b ABL isoforms binds to a hydrophobic pocket within the C-lobe of the kinase domain, stabilizing the auto-inhibited conformation. The configuration and interactions of the ABL C-terminal sequences are not included in the model. The kinase selectivity profiles for imatinib, nilotinib, and dasatinib were generated based on the binding of cellular kinases to inhibitors immobilized on solid support matrices reviewed previously in Ponatinib-sensitive kinases were identified by in vitro kinase assays; shown are targets with IC 50 values of less than 20 nM The catalytic activities of the ABL kinases are tightly regulated by inter- and intramolecular interactions and post-translational modifications Fig. This topic has been extensively reviewed and thus will only be briefly discussed here 5 , 6 , Among prominent intramolecular interactions required for autoinhibition are those involving the SH3 and SH2 domains 35 Fig. Autoinhibition is also mediated by the binding of the myristoylated residue in the ABL N-terminus to a hydrophobic pocket within the C-lobe of the kinase domain This interaction stabilizes the autoinhibited conformation of the myristoylated 1b isoform of the ABL kinase Fig. Inhibitory intramolecular interactions that stabilize the 1a isoform of ABL are poorly understood and may involve binding to lipid residues in trans. ABL activity can be negatively or positively regulated by intermolecular interactions with distinct binding partners. In general, intermolecular interactions that disrupt autoinhibitory interactions and stabilize the active open conformation of the ABL kinases promote increased enzymatic activity. Intermolecular interactions that stabilize the inactive conformation of the ABL kinases inhibit enzymatic activity and downstream signaling. The enzymatic activity of the ABL kinases is also regulated by tyrosine phosphorylation. Phosphorylation of these tyrosines stabilizes the active conformation of the ABL kinases, and can occur by transphosphorylation between ABL proteins or may be mediated by Src family kinases The stability of ABL kinases can be modulated by tyrosine phosphorylation. Phosphorylation of ABL1 on Y and Y decreases protein stability through ubiquitination and subsequent degradation by the 26S proteasome machinery The role of the BCR-ABL1 fusion proteins in the initiation and progression of leukemia has been extensively covered in previous reviews and will not be discussed here 48 , Inhibitors of the ABL kinases are classified into three main classes based on their mechanism of action: type 1 inhibitors target the active conformation of the kinase domain dasatinib, bosutinib , whereas type 2 inhibitors stabilize the inactive conformation of the kinase domain preventing its activation imatinib, nilotinib, ponatinib. The third category of inhibitors includes allosteric inhibitors which do not compete for ATP binding, but rather bind to regulatory domains to inhibit kinase activity Figs. In contrast to the ATP-competitive inhibitors that target multiple kinases, the allosteric inhibitors are highly selective for the ABL kinases Fig. These allosteric inhibitors decrease BCR-ABL1 enzymatic activity and inhibit BCR-ABL1-driven leukemogenesis in mice 56 ; thus underscoring the importance of intramolecular autoinhibitory mechanisms regulating kinase activity of the oncogenic fusion protein. While imatinib has proven an effective drug for patients with CML, up to one-third of CML patients require alternate therapies Second-generation inhibitors such as nilotinib Tasigna, AMN; Novartis , which inhibits ABL kinases at to fold lower concentrations than imatinib, are used to treat imatinib-resistant disease Similar to dasatinib and bosutinib, ponatinib has broad target specificity Fig. Schematic representation of ABL1, and the various ABL1 and ABL2 fusion proteins that arise as a consequence of chromosome translocations in various types of human leukemia. The coiled-coil CC and other motifs in the fusion partner promote oligomerization of the resulting chimeric ABL kinases. The v-Abl1 oncoprotein fuses Gag sequences of Abelson murine leukemia virus to sequences upstream of the Abl1 SH2 domain 57 , In general, the fusion partners encode proteins that contain coiled-coil or helix-loop-helix motifs that promote oligomerization of the resulting chimeric ABL kinases. Alterations in ABL1 or ABL2 are also found in skin cutaneous melanoma, bladder urothelial carcinoma, colorectal adenocarcinoma, rhabdoid tumors, as well as renal medullary and clear cell renal carcinoma cbioportal. These findings are consistent with earlier reports of elevated ABL2 expression in advanced high-grade colorectal, pancreatic, renal and gastric tumors, implicating an association between ABL2 activity and tumor progression 21 , 63 - The prevalence of ABL2 amplification and enhanced gene expression are comparable to those reported for several kinases previously implicated in breast invasive carcinoma TCGA; Somatic mutations of ABL1 and ABL2 in solid tumors are rare, but have been reported in selected solid tumors, including lung cancer and uterine corpus endometroid carcinoma 66 - 69 , cbioportal. The role of these mutations in regulating ABL oncogenic activity remains to be determined. Data compiled from The Cancer Genome Atlas 18 cbioportal. For each cancer type, the number of cases is shown in parenthesis. Subsequent studies demonstrated that ABL kinases are tyrosine phosphorylated and activated in breast, lung, colorectal, gastric, and prostate cancer cells as well as in melanoma 8 - Analysis of global tyrosine phosphorylation profiles of lung cancer cells showed higher levels of ABL tyrosine phosphorylation, but the identity of the upstream signals promoting tyrosine phosphorylation of the ABL kinases, and their role in the initiation and progression of lung tumors is largely unknown 10 - In solid tumor cells, ABL activation has often been linked to stimulation by hyperactive RTKs and chemokine receptors 8 , Thus, the catalytic activity of the ABL kinases can be up-regulated by ligand-dependent and ligand-independent activation of RTKs. In addition to activation by upstream kinases, ABL kinases can also be activated through the inactivation of negative regulatory networks including interactions with inhibitory proteins. In this regard, activation of ABL1 in two lung adenocarcinoma cell lines correlated with loss of the tumor suppressor protein FUS NA: Not Applicable. Activation of ABL kinases in solid tumor types has been linked to alterations in cell growth and survival. Several studies have reported inhibitory effects of imatinib, nilotinib and related ABL TKIs Box 1 on cancer cell proliferation and survival in vitro and in xenograft studies, but the cellular responses to these compounds cannot be solely attributed to inhibition of the ABL kinases as these compounds have numerous kinase and some non-kinase targets 75 , 76 Fig. Depletion of either ABL1 or ABL2 with specific siRNAs in breast cancer cells that express elevated levels of one or both proteins showed that both kinases were required for anchorage-independent growth Both ABL kinases were also required for maximal proliferation of melanoma cell lines Additionally, depletion of ABL2 alone in non-small cell lung cancer lines decreased cell growth 77 , and ABL1 alone was required for survival and anchorage-independent growth of gastric and hepatocellular carcinoma cells While ABL kinases promote cell proliferation and survival in leukemias and some solid tumor cell lines, three reports have shown that ABL kinases suppress the growth of breast cancer xenografts 82 - Stimulation of the EphB4 receptor with ephrin-B2 in breast cancer cells decreased cell growth through an ABL-CRK pathway, and imatinib blocked the inhibitory effect of ephrin-B2 on the growth of these breast cancer xenografts ABL1 and ABL2 have overlapping functions during cell proliferation in some cell types, but the consequences of depleting both kinases on the growth of the MDA-MB xenograft tumors was not reported in this study A role for ABL kinases in the growth of mammary tumors may depend on the cellular context, the repertoire of oncogenes and tumor suppressors expressed in the tumor, redundancy in the function of ABL1 and ABL2 kinases, and upstream signals that regulate tumor suppressive versus promoting pathways in distinct cell lines. ABL kinases can be activated in response to distinct types of cellular stress including those mediated by reactive oxygen species ROS 86 - Elevated levels of ROS are a feature characteristic of many solid tumors 90 , 91 and are also an inevitable by-product of cellular metabolism. High levels of ROS can induce cell death, whereas lower chronic levels of ROS may induce inflammation, promote tumorigenesis, and other disease states Oxidative stress results when the level of oxidants within the cells supersedes the antioxidant defense and may be induced by exogenous as well as endogenous sources Due to increased cellular metabolism, cancer cells are vulnerable to oxidative stress as the antioxidant defense system may be operating at its maximum threshold ABL2 was reported to promote cell survival in response to low levels of oxidative stress, but high levels of oxidative stress correlated with ABL2 degradation and apoptosis 95 , ABL1 was shown to enhance cell proliferation of fibroblasts lacking p53 under non-stress conditions 99 , Interestingly, ABL1 can differentially modulate p53 activity and cellular responses through alteration of Mdm2, a regulator and transcriptional target of p Mechanistically, ABL1 protects p53 from the inhibitory effect of Mdm2, by promoting Mdm2 tyrosine phosphorylation, which restricts its interactions with p53, allowing for the accumulation of p53 and the promotion of apoptosis under stress conditions Recently, ABL1 was shown to be required for cell survival and activation of a p38 MAP kinase-pMdm2 pathway in response to ligand-activated Met kinase in hepatocellular carcinoma cells Thus, ABL kinases can differentially disrupt the pMdm2 regulatory loop to suppress or promote cell growth and survival depending on the upstream signals leading to ABL activation and the cellular context. In addition to oxidative stress, growth factor deprivation was reported to activate ABL1 in mammary epithelial cells by inducing binding to the Mig6 ERRFI1 adaptor and triggering pdependent apoptosis Silencing ABL1 in primary mammary epithelial cells pMECs in 3D cultures impaired lumen formation, which may be due, in part, to decreased cell death However, in comparison to wild-type pMECs, the ABL1-depleted pMECs failed to reconstitute the mammary gland after transplantation into the cleared mouse fat pads, suggesting impaired cell proliferation in the absence of ABL1 Disruption of cell polarity is an early event in the evolution of epithelial tumors A role for ABL kinases in the regulation of epithelial apical-basal polarity was first described in Drosophila - Furthermore, expression of activated ABL2, and to a lesser extent ABL1, induces a striking inversion of apical-basal polarity in epithelial cells grown in a 3D cell culture system in the presence of collagen Fig. Thus, ABL kinases may contribute to loss of epithelial polarity at early stages of tumor development. Epithelial cells expressing control vector or constitutively active forms of the ABL kinases were grown in collagen gels and stained for the apical polarity marker gp, the adherens junction marker E-cadherin and the nuclear DAPI stain. Model for the inversion of epithelial cell polarity by active ABL kinase. Active ABL2 also impairs Rac1-mediated laminin assembly in epithelial cysts Spindle orientation is important for morphogenesis, asymmetric cell division and stem cell self-renewal, processes that are deregulated during tumorigenesis - Notably, a recent report showed that ABL1 regulates spindle orientation in epithelial cells in culture and the mouse epidermis Whether the ABL1-induced changes in spindle orientation contributes to tumor progression remains to be determined. The progression of solid tumors involves dramatic changes in cell morphology, adhesion, motility and polarity that are dependent on cytoskeletal rearrangements. Epithelial tumors can activate dormant developmental pathways that promote conversion from organized epithelial tissue into isolated cells with mesenchymal morphology through the Epithelial-to-Mesenchymal Transition EMT program , EMT is characterized by loss of cell polarity, disassembly of cell-cell junctions, acquisition of mesenchymal cell morphology and gene expression profiles, together with enhanced cell motility and invasion. Notably, these cellular processes are linked to signaling networks regulated by ABL family kinases. Consequently, depletion and pharmacological inhibition of ABL kinases in colon and cervical cancer cells promoted epithelial phenotypes in cells that had been induced to undergo EMT 9 , The role of ABL1 in EMT may be context-dependent, however, as pharmacological inhibition or silencing of ABL kinases in normal epithelial cells results in dissolution of cell-cell junctions without inducing expression of genes required for the EMT program 32 , Interestingly, alternative splicing promoted by EMT in breast cancer cells results in the formation of a spliced ABL2 isoform predominantly expressed in mesenchymal cells The EMT program is linked to acquisition of therapeutic resistance in solid tumors , and ABL signaling has recently been shown to be up-regulated in chemoresistant breast tumors Tumor progression and metastasis require the induction of an invasive program that promotes dissemination into surrounding tissues by primary tumor cells, followed by intravasation, migration, extravasation, and formation of metastases at distant sites ABL kinases engage the actin polymerization machinery in response to growth factor and chemokine stimulation as well as adhesion cues, and promote formation of membrane protrusions, morphological changes, altered cell adhesion, migration and invasion of diverse cell types 6 , 37 , 54 , ABL kinases are required for cell motility and invasion induced by IGF-1, EGF, serum and chemokines in breast, hepatocellular carcinoma, and melanoma cells 8 , 16 , 33 , 73 , 84 , ABL kinases can regulate invasion by directly phosphorylating proteins required for invasive behavior, and also by regulating the expression of genes linked to invasion and cell motility Fig. ABL2 localizes to invadopodia, where it is required for both matrix degradation and invasion in breast cancer cells 33 , In addition to cortactin, other actin regulatory proteins are targeted by ABL kinases at invadopodia Fig. Active ABL2 interacts with and promotes phosphorylation of the membrane type 1-matrix metalloproteinase MT1-MMP, also known as MMP14 and is required for its localization and function at invadopodia The HEF1 protein also regulates cancer cell invasion, and ABL-mediated phosphorylation of HEF1 may be required for promoting invasive behavior as observed during chemokine-induced T cell migration Consistent with its ability to positively regulate invadopodia formation and function, knockdown of ABL2 decreased cancer cell invasion and intravasation following implantation of MDA-MB cells in the mammary fat pad One or both ABL kinases are required for cancer cell invasion depending on the cellular context 16 , Solid lines indicate direct links between ABL and target proteins; dotted lines indicate indirect links. The pharmacology and clinical data of these drugs has been recently reviewed While imatinib has proven remarkably successful for the treatment of CML, particularly those in chronic phase, up to one-third of patients will require alternative therapies The effectiveness of imatinib decreases during the acute and blast stages of CML. Development of imatinib resistance may result from the development of mutations in BCR-ABL1 that alter drug binding, including the TI gatekeeper mutation. Newer allosteric inhibitors have been tested in preclinical models of resistance; among these are the GNF-2 and GNF-5 allosteric inhibitors that target the myristate pocket of ABL kinases Fig. Thus, the combined use of allosteric and ATP competitive inhibitors may represent an effective strategy to overcome resistance to either type of compound alone. In contrast to the success of TKI therapies for the treatment of BCR-ABL1-induced leukemias, use of the ATP-competitive inhibitors imatinib, nilotinib and dasatinib has not achieved similar success for the treatment of solid tumors reviewed in , The variable clinical responses to these TKIs may reflect the heterogeneous nature of solid tumors, which often have acquired mutations in multiple tumor promoting pathways. In addition, recent work has shown that signaling networks can be rewired in response to treatment with single kinase inhibitors , , which may underlie poor responses to treatment. Another mechanism that underlies the poor response to TKI therapy in some solid tumors and chemoresistant leukemias is the targeting of alternative pathways resulting in paradoxical activation of proliferative pathways. Therefore, the indiscriminate use of imatinib, nilotinib, dasatinib and other ABL-targeted ATP-competitive TKIs is not recommended; rather, screening tumors for ABL amplification, enhanced expression and hyperactivation, as well as co-expression of other mutations associated with poor response to specific TKIs, is crucial for identifying those tumors that may benefit from therapies with selective ABL TKIs. Additionally, developing an ABL signature genomic, transcriptional, or phospho-proteomic might be critical to identify subset of patients to rationally test the effects of these inhibitors. One interesting possibility for the future of ABL TKIs in cancer therapy may lie in overcoming resistance to chemotherapies. Enhanced expression of ABL1 signaling networks was recently detected in endocrine-resistant breast cancer Treatment of breast cancer cells with imatinib has been shown to sensitize these cells to selected drugs such as 5-fluorouracil, cisplatin and vinorelbine , Furthermore, imatinib treatment or ABL1 depletion was shown to restore sensitivity to the EGFR and ErbB2 inhibitor lapatinib in breast cancer cells that had acquired lapatinib-resistance Future studies are warranted to define how ABL1 inhibition sensitizes cancer cells to chemotherapies and whether such an approach may improve the effectiveness of chemotherapy in vivo. While the ABL1 kinase was first linked to the induction of human leukemia almost three decades ago 2 , a role for ABL family kinases in the progression of solid tumors has only recently been recognized. Over the last decade the use of imatinib, dasatinib and nilotinib to treat patients with BCR-ABL1-positive leukemias provided the best example for the successful use of TKI-targeted therapy. However, it is clear that the use of these drugs is inadequate for the treatment of solid tumors as monotherapies due to the complexity of mutations even in early-stage tumors, and the potential for inappropriate activation rather than inhibition of proliferative pathways by some TKIs with multiple protein targets. Ongoing preclinical and future clinical studies are expected to evaluate whether treatment of patients with tumors with ABL amplification, enhanced expression and hyper-activation could benefit from therapies with ABL-selective TKIs. The identification of new allosteric inhibitors with greater specificity against ABL family kinases may allow for evaluation of the effectiveness of targeting these kinases in the treatment of solid tumors with hyperactive ABL kinases, and whether anti-ABL therapies display greater effectiveness at specific tumor stages. Recent findings suggest that ABL1 and ABL2 may regulate overlapping as well as distinct cellular processes in various cell types, and may differentially contribute to tumor progression. Future studies will be required to evaluate unique roles for the ABL kinases not only in selected solid tumors, but also in cells in the tumor microenvironment. ABL kinases regulate diverse signaling pathways in fibroblasts, macrophages, and T cells 34 , 54 , 70 , , , These cell types are known to contribute to tumor progression and metastasis in various cancers - , and a role for ABL kinases in tumor-promoting pathways in distinct cell types in the microenvironment should be an area of active enquiry. Exciting research over the next few years is expected to evaluate the contribution of ABL kinases to distinct tumor types and establish whether these kinases prove to be useful targets for the treatment of multiple solid tumor types. The authors regret that due to space limitations, they could not directly cite the work of many investigators. We thank Ran Li for confocal images. Sci Rep , 14 1 , 01 Oct Cited by: 0 articles PMID: Nat Commun , 15 1 , 11 Sep Curr Oncol , 31 9 , 23 Aug Sci Rep , 14 1 , 07 Aug Refer to the copyright information in the article for licensing details. Free full text in Europe PMC. Chawhan AP , Dsouza N. Mol Genet Genomics , 1 , 03 Aug To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation. J Cell Sci , 1 , 01 Jan Lancet Haematol , 8 1 :ee66, 22 Dec Wang JY. Mol Cell Biol , 34 7 , 13 Jan Arterioscler Thromb Vasc Biol , 35 5 , 26 Mar Europe PMC requires Javascript to function effectively. Search life-sciences literature 44,, articles, preprints and more Search Advanced search. This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy. Greuber EK 1 ,. Smith-Pearson P ,. Wang J ,. Pendergast AM. Affiliations 1. Authors Greuber EK 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract The Abelson ABL family of nonreceptor tyrosine kinases, ABL1 and ABL2, transduces diverse extracellular signals to protein networks that control proliferation, survival, migration and invasion. ABL1 was first identified as an oncogene required for the development of leukaemias initiated by retroviruses or chromosome translocations. The demonstration that small-molecule ABL kinase inhibitors could effectively treat chronic myeloid leukaemia opened the door to the era of targeted cancer therapies. Recent reports have uncovered roles for ABL kinases in solid tumours. Enhanced ABL expression and activation in some solid tumours, together with altered cell polarity, invasion or growth induced by activated ABL kinases, suggest that drugs targeting these kinases may be useful for treating selected solid tumours. Free full text. Nat Rev Cancer. Author manuscript; available in PMC Feb PMID: Emileigh K. Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Nat Rev Cancer. See other articles in PMC that cite the published article. Go to:. Open in a separate window. Figure 1. Modular domain structure of ABL family kinases A. Figure 2. ABL activation by chromosome translocations in leukemia Schematic representation of ABL1, and the various ABL1 and ABL2 fusion proteins that arise as a consequence of chromosome translocations in various types of human leukemia. ABL in cell polarity Disruption of cell polarity is an early event in the evolution of epithelial tumors Figure 3. ABL in Epithelial-to-Mesenchymal Transition The progression of solid tumors involves dramatic changes in cell morphology, adhesion, motility and polarity that are dependent on cytoskeletal rearrangements. Role of ABL kinases during invasion and metastasis Tumor progression and metastasis require the induction of an invasive program that promotes dissemination into surrounding tissues by primary tumor cells, followed by intravasation, migration, extravasation, and formation of metastases at distant sites Figure 4. Use of ABL kinase inhibitors for solid tumors: past and future In contrast to the success of TKI therapies for the treatment of BCR-ABL1-induced leukemias, use of the ATP-competitive inhibitors imatinib, nilotinib and dasatinib has not achieved similar success for the treatment of solid tumors reviewed in , Competing Interests Statement The authors declare no competing financial interests. Structure of the Abelson murine leukemia virus genome and the homologous cellular gene: studies with cloned viral DNA. Lin J, Arlinghaus R. Activated c-Abl tyrosine kinase in malignant solid tumors. The Abl family kinases: mechanisms of regulation and signaling. Cancer Res. Colicelli J. 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Abl family tyrosine kinases are essential for basement membrane integrity and cortical lamination in the cerebellum. Li B, et al. Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Nature Genetics. Kua HY, et al. Cell Biol. Koleske AJ, et al. Essential roles for the Abl and Arg tyrosine kinases in neurulation. Loss of dendrite stabilization by the Abl-related gene Arg kinase regulates behavioral flexibility and sensitivity to cocaine. Van Etten RA, et al. The Abl-related gene Arg nonreceptor tyrosine kinase uses two F-actin-binding domains to bundle F-actin. The Abl-related gene Arg requires its F-actin-microtubule cross-linking activity to regulate lamellipodial dynamics during fibroblast adhesion. Abl tyrosine kinases regulate cell-cell adhesion through Rho GTPases. Abl kinases are required for invadopodia formation and chemokine-induced invasion. Abl family kinases regulate FcgammaR-mediated phagocytosis in murine macrophages. Hantschel O, Superti-Furga G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Hantschel O, et al. Plattner R, et al. A new link between the c-Abl tyrosine kinase and phosphoinositide signalling through PLC-gamma1. Enhancement of ABL kinase catalytic efficiency by a direct binding regulator is independent of other regulatory mechanisms. The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes Dev. Cong F, et al. Two distinct phosphorylation pathways have additive effects on Abl family kinase activation. Echarri A, Pendergast AM. Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway. Wong S, Witte ON. Kantarjian HM, et al. Significance of the P versus P molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia. Suryanarayan K, et al. Consistent involvement of the bcr gene by 9;22 breakpoints in pediatric acute leukemias. Pane F, et al. Wilson G, et al. Ren R. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Muller AJ, et al. Titz B, et al. Targeting cancer with small molecule kinase inhibitors. Zhang J, et al. Hagemeijer A, Graux C. ABL1 rearrangements in T-cell acute lymphoblastic leukemia. Genes, Chromosomes and Cancer. De Braekeleer E, et al. ABL1 fusion genes in hematological malignancies: a review. European Journal of Haematology. Ernst T, et al. British Journal of Haematology. ETV6 fusion genes in hematological malignancies: a review. De Keersmaecker K, et al. Koos B, et al. The tyrosine kinase c-Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors. Chen G, et al. Crnogorac-Jurcevic T, et al. Expression profiling of microdissected pancreatic adenocarcinomas. Wu CW, et al. Arg tyrosine kinase expression in human gastric adenocarcinoma is associated with vessel invasion. Anticancer Research. Greenman C, et al. Patterns of somatic mutation in human cancer genomes. Ruhe JE, et al. Genetic alterations in the tyrosine kinase transcriptome of human cancer cell lines. Ding L, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Hammerman PS, et al. Comprehensive genomic characterization of squamous cell lung cancers. The tyrosine kinase Abl is required for Src-transforming activity in mouse fibroblasts and human breast cancer cells. Aggressive breast cancer cells are dependent on activated Abl kinases for proliferation, anchorage-independent growth and survival. Mader CC, et al. ABL2 localizes to invadopodia and regulates the function of invadopodia components including cortactin and MT1-MMP in breast cancer cells. Iavarone C, et al. Packer LM, et al. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cytoplasmic signalling by the c-Abl tyrosine kinase in normal and cancer cells. Biologie Cellulaire. WNT signalling pathways as therapeutic targets in cancer. Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. The Hippo pathway and human cancer. The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Activated Abl kinase inhibits oncogenic transforming growth factor-beta signaling and tumorigenesis in mammary tumors. Gil-Henn H, et al. Li X, et al. Shaul Y, Ben-Yehoyada M. Role of c-Abl in the DNA damage stress response. Cell Res. Sun X, et al. Activation of the cytoplasmic c-Abl tyrosine kinase by reactive oxygen species. Cao C, et al. The ARG tyrosine kinase interacts with Siva-1 in the apoptotic response to oxidative stress. Hopkins S, et al. Mig6 is a sensor of EGF receptor inactivation that directly activates c-Abl to induce apoptosis during epithelial homeostasis. Redox metabolism and malignancy. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. The role of oxidative stress in carcinogenesis. Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity. Cancer Chemother. Ubiquitination and degradation of the Arg tyrosine kinase is regulated by oxidative stress. Functional interaction between the c-Abl and Arg protein-tyrosine kinases in the oxidative stress response. Kharbanda S, et al. Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Yuan ZM, et al. Role for c-Abl tyrosine kinase in growth arrest response to DNA damage. Whang YE, et al. Furstoss O, et al. EMBO J. Goldberg Z, et al. Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation. Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Levav-Cohen Y, et al. C-Abl as a modulator of p Polarity proteins regulate mammalian cell-cell junctions and cancer pathogenesis. Baum B, Perrimon N. Spatial control of the actin cytoskeleton in Drosophila epithelial cells. Abelson kinase regulates epithelial morphogenesis in Drosophila. Fox DT, Peifer M. Abl regulates planar polarized junctional dynamics through beta-catenin tyrosine phosphorylation. Drosophila Abelson kinase mediates cell invasion and proliferation through two distinct MAPK pathways. Li R, Pendergast AM. Arg kinase regulates epithelial cell polarity by targeting beta1-integrin and small GTPase pathways. Thus, activated ABL kinases may be involved in early steps of tumor initiation. Quyn AJ, et al. Spindle orientation bias in gut epithelial stem cell compartments is lost in precancerous tissue. Cell Stem Cell. Gonzalez C. Spindle orientation, asymmetric division and tumour suppression in Drosophila stem cells. Molecular Carcinogenesis. Knoblich JA. Mechanisms of asymmetric stem cell division. Matsumura S, et al. ABL1 regulates spindle orientation in adherent cells and mammalian skin. Lechler T, Fuchs E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Suh Y, et al. Claudin-1 induces epithelial-mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells. Shapiro IM, et al. An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet. Weigel MT, et al. Annals of Oncology. Fidler IJ. Yoon CH, et al. Claudin-1 acts through c-Abl-protein kinase Cdelta PKCdelta signaling and has a causal role in the acquisition of invasive capacity in human liver cells. Abl interactor 1 regulates Src-Id1-matrix metalloproteinase 9 axis and is required for invadopodia formation, extracellular matrix degradation and tumor growth of human breast cancer cells. Oser M, et al. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. Specific tyrosine phosphorylation sites on cortactin regulate Nck1-dependent actin polymerization in invadopodia. Cell Biochemistry and Biophysics. Roychowdhury S, Talpaz M. Managing resistance in chronic myeloid leukemia. Blood Reviews. Grebien F, et al. Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis. Ganguly SS, Plattner R. Activation of abl family kinases in solid tumors. Genes Cancer. Current status of SRC inhibitors in solid tumor malignancies. The Oncologist. Lee MJ, et al. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Duncan JS, et al. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Su F, et al. Breast Cancer Res. He X, et al. Zhao H, et al. Enhanced resistance to tamoxifen by the c-ABL proto-oncogene in breast cancer. Sims JT, et al. STI sensitizes breast cancer cells to 5-fluorouracil, cisplatin and camptothecin in a cell type-specific manner. Biochemical Pharmacology. Combination of imatinib and vinorelbine enhances cell growth inhibition in breast cancer cells via PDGFR beta signalling. Cancer Letters. The Abl and Arg kinases mediate distinct modes of phagocytosis and are required for maximal Leishmania infection. Defective T cell development and function in the absence of Abelson kinases. Orimo A, Weinberg RA. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle. Pollard JW. Trophic macrophages in development and disease. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer and Metastasis Reviews. Millot F, et al. Imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: results of the French national phase IV trial. Journal of Clinical Oncology. Schultz KR, et al. Bianchi C, et al. Eight full-length abelson related gene Arg isoforms are constitutively expressed in caki-1 cell line and cell distribution of two isoforms has been analyzed after transfection. Cell Biochem. Adrian FJ, et al. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Choi Y, et al. N-myristoylated c-Abl tyrosine kinase localizes to the endoplasmic reticulum upon binding to an allosteric inhibitor. Lymphosarcoma: virus-induced thymic-independent disease in mice. Multiple steps are required for the induction of tumors by Abelson murine leukemia virus. Preliminary identification of somatic mutations profile in ACL injury. Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets. Identifying the key hub genes linked with lung squamous cell carcinoma by examining the differentially expressed and survival genes. Similar Articles To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation. Multifunctional Abl kinases in health and disease. Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort study. The capable ABL: what is its biological function? Targeting Abl kinases to regulate vascular leak during sepsis and acute respiratory distress syndrome. Funding Funders who supported this work. External link. Please review our privacy policy. Uterine Corpus Endometrioid Carcinoma Ovarian Serous Cystadenocarcinoma Cytosolic Actin cytoskeleton Nuclear. Cytosolic Actin cytoskeleton. Regulated disruption of intramolecular interactions Reversible tyrosine phosphorylation. Oligomerization Disruption of inhibitory intramolecular interactions by BCR sequences Constitutive tyrosine phosphorylation. Upstream Signals Leading to Reversible Activation. Intercellular adhesion structures that tightly seal the lateral spaces between cells in simple epithelia. Epithelial cells are polarized, with an apical membrane that faces the external environment or a lumen and is opposite the basolateral membrane, which functions in cell—cell interactions and contacts the basement membrane. An excess of reactive oxygen species ROS , caused by an imbalance between the rate of reduction and oxidation of oxygen, leading to free radical generation and damage to cellular components such as DNA and lipids. SRC homology-2 domain is a protein module that binds to tyrosine phosphorylated sites in a sequence-specific context.

2014 Giro d'Italia route presented in Milan

Ponte di Legno where can I buy cocaine

Our community members are treated to special offers, promotions and adverts from us and our partners. You can check out at any time. More info. The slopes of Passo Tonale in Italy were ready and calling as I returned to skiing with Crystal Ski after an, ahem, extended break. Located in the Dolomites, the snow-sure resort at 1, metres is popular with families and beginners with miles of rolling blue slopes which made it the perfect spot to rediscover my love of skiing after more than a decade away from the slopes. Passe Tonale is a purpose-built resort, with the majority of the hotels, bars and shops along one road, which sits at the bottom of a row of ski runs. It is therefore easy to find your way around with everything within an easy walking distance of around 3km. The small town centre is quaint and charming with traditional Alpine-style buildings housing hotels, restaurants and quaint gift shops, including a fabulous chocolate shop complete with chocolate fountain and handmade gelato which should not be missed. Passe Tonale straddles the mountain pass that links the Trentino and Lombardy regions of Italy, and at more than 1, metres is high enough for great snow conditions all winter usually until the end of April. The town is linked to neighbouring Ponte Di Legno - a larger town with a more traditional European focused layout around a main square - by ski runs, road and by gondola. With km of mainly intermediate and easy runs, including a row of half a dozen shorter runs right in front of the town centre, Passe Tonale is an ideal resort for families and beginners, or those finding their ski legs again after a break like me. In total there are nine easy blue runs, 25 intermediate red runs and seven black runs in the resort. With long, rolling and scenic blue runs, including a glacier blue run, there were more than enough easy slopes to fill several days of skiing before I felt confident enough to try out a red run. There were also no queues at any of the chairlifts at all while I was there in the last week of January. After a couple of hours with a ski school instructor, I was ready to make my own way and found the resort really easy to navigate using the piste map in the Crystal ski explorer app. A five minute walk from the main ski area is the gondola to the glacier ski area at 3, metres. At the top of the glacier is a long blue run, two red runs, three restaurants and gondola stops, with a black run which joins a red run linking to the more challenging Ponte Di Legno skiing area. As a returning skier, with far from expert skills, the runs offered the perfect balance of scenic and enjoyable easy routes, with options to challenge and improve for intermediate skiers. I stayed at The Grand Hotel Paradiso which oozes chic, with a modern neutral colour palette and huge floor to ceiling windows to take in the uninterrupted mountain landscape which surrounds the hotel. Set slightly away from the main strip of hotels, the stylish hotel is on the side of town closest to the gondolas less than a five minute walk , and has ski-in and -out access at the top of a flight of stairs outside the hotel. The neutral, unstated classy decor continues into the huge bedrooms, which have floor to ceiling windows with balconies to enjoy the stunning sunset views. The hotel boasts a boutique spa area in the basement with a pool, steam rooms and sauna which was delightful after a long day on the slopes. And in-keeping with the family-friendly resort the hotel has kids-clubs and games room. Of the half dozen bars and restaurants at the foot of the slopes in the town centre, La Baracca is the pick of the bunch. The glass-fronted restaurant has amazing views across the slopes, especially the sunny day we visited, and offers table service for just a few euros more per dish than the more typical self-service restaurants nearby. Away from the hotel La Torretta Cucina Pizza is an excellent choice for traditional Trentinto food - think Italian meets Germanic gastronomy, with meat stews, dumplings, polenta, pasta and antipasti jostling for space on an expansive menu. For an extra special treat we sampled a four course Trentino tasting menu in a 12th Century former monastery at the Hotel La Mirandola, which was spectacular. Although the Apres ski is still not as lively as pre-pandemic due to covid restrictions, there are still a number of bars at the bottom of the slopes pumping out loud music and large Aperol Spritz to happy skiers. The Italian skier's reward of choice is a bombardino drink made with Advocaat or eggnog mixed with rum or brandy served warm and I can vouch for its popularity. An NHS covid pass confirming that you have had one dose of the vaccine either a booster jab, first or second jab within the past six months, is valid as a green pass in Italy. Looking for an Apres-ski activity away from the bars? I can highly recommend night snowmobiling. A guided tour takes you speeding up the slopes in the main ski areas, along the tree-lined route to Ponte Di Legno before a speedy ascent back to the town centre and is great fun. Selected Passe Tonale ski passes include one day of skiing in another resort within the region and after a couple of days in the resort we headed out on a ski away day to Madonna di Campiglio. Prices provided are subject to change and have limited availability. Terms and conditions apply. What's On. By Laura Hill. Get the latest Wales Online breaking news on WhatsApp. Join us on WhatsApp. After a slightly stuttered start to the season, ski resorts are now back to almost full swing. The resort Passe Tonale is a purpose-built resort, with the majority of the hotels, bars and shops along one road, which sits at the bottom of a row of ski runs. Story Saved. Follow Wales Online. Facebook Twitter. More On tendendo. Alanis Morissette announces Cardiff date for world tour. Major high street chain to close all branches for three days over Christmas period. Huge queues form in the middle of Cardiff as people scramble to try new foodie spot. Your Money. Welsh pub named among the most haunted places in the world by Time Out. Essential Wales. Sleep expert says parents need to make minute change tomorrow. Roman skirt in trending colour that's perfect for 'autumn and winter' is selling fast. Police investigate unexplained death of woman in Welsh town. Wales autumn squad: Scrum-half recalled 10 years after last cap and England U20s star picked. Wales Rugby Team. Boss laid off member of staff because she came back from maternity leave pregnant again. Strictly Come Dancing. Nearly 10, complaints made to Ombudsman about councils in Wales last year. Local Government. Warren Gatland names 'best back in Wales' as he hints at change of heart. Police probe death of loving father who died in military exercise in Wales. Brecon Beacons. Top Stories. Woman taken to hospital after emergency services shut Cardiff city centre bridge. Man arrested at Bristol Airport in connection with alleged baseball bat attack at football match. Police caught him after he boasted to his ex-partner about how much money he was making. Man who hasn't left home in years just wants to be able to 'go to the chippy'. UK News. Man suffers multiple head injuries after alleged assault. This is Gatland's most exciting squad for some time but Wales must now find right balance. Cardiff Airport. Three left in need of help off Welsh coast as Storm Ashley hits. Wales weather. Series of closures on M4 Prince of Wales bridge set to bring disruption for motorists. Traffic and Travel.

Ponte di Legno where can I buy cocaine