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Development of Erasin: a chromone-based STAT3 inhibitor which induces apoptosis in Erlotinib-resistant lung cancer cells.
Lis C, Rubner S, Roatsch M, Berg A, Gilcrest T, Fu D, Nguyen E, Schmidt AM, Krautscheid H, Meiler J, Berg T
(2017) Sci Rep 7: 17390
MeSH Terms: Antineoplastic Agents, Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Chromones, Humans, Lung Neoplasms, Molecular Docking Simulation, Phosphorylation, Protein Processing, Post-Translational, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, Structure-Activity Relationship, Tumor Suppressor Proteins, src Homology Domains
Show Abstract · Added March 17, 2018
Inhibition of protein-protein interactions by small molecules offers tremendous opportunities for basic research and drug development. One of the fundamental challenges of this research field is the broad lack of available lead structures from nature. Here, we demonstrate that modifications of a chromone-based inhibitor of the Src homology 2 (SH2) domain of the transcription factor STAT5 confer inhibitory activity against STAT3. The binding mode of the most potent STAT3 inhibitor Erasin was analyzed by the investigation of structure-activity relationships, which was facilitated by chemical synthesis and biochemical activity analysis, in combination with molecular docking studies. Erasin inhibits tyrosine phosphorylation of STAT3 with selectivity over STAT5 and STAT1 in cell-based assays, and increases the apoptotic rate of cultured NSCLC cells in a STAT3-dependent manner. This ability of Erasin also extends to HCC-827 cells with acquired resistance against Erlotinib, a clinically used inhibitor of the EGF receptor. Our work validates chromone-based acylhydrazones as privileged structures for antagonizing STAT SH2 domains, and demonstrates that apoptosis can be induced in NSCLC cells with acquired Erlotinib resistance by direct inhibition of STAT3.
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16 MeSH Terms
The Cdc15 and Imp2 SH3 domains cooperatively scaffold a network of proteins that redundantly ensure efficient cell division in fission yeast.
Ren L, Willet AH, Roberts-Galbraith RH, McDonald NA, Feoktistova A, Chen JS, Huang H, Guillen R, Boone C, Sidhu SS, Beckley JR, Gould KL
(2015) Mol Biol Cell 26: 256-69
MeSH Terms: Amino Acid Sequence, Cell Cycle Proteins, Cell Division, Cytokinesis, Cytoskeletal Proteins, GTP-Binding Proteins, Gene Regulatory Networks, Guanine Nucleotide Exchange Factors, Immunoblotting, Luminescent Proteins, Microscopy, Confocal, Molecular Sequence Data, Mutation, Protein Binding, Proteome, Proteomics, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Sequence Homology, Amino Acid, Time-Lapse Imaging, src Homology Domains
Show Abstract · Added January 20, 2015
Schizosaccharomyces pombe cdc15 homology (PCH) family members participate in numerous biological processes, including cytokinesis, typically by bridging the plasma membrane via their F-BAR domains to the actin cytoskeleton. Two SH3 domain-containing PCH family members, Cdc15 and Imp2, play critical roles in S. pombe cytokinesis. Although both proteins localize to the contractile ring, with Cdc15 preceding Imp2, only cdc15 is an essential gene. Despite these distinct roles, the SH3 domains of Cdc15 and Imp2 cooperate in the essential process of recruiting other proteins to stabilize the contractile ring. To better understand the connectivity of this SH3 domain-based protein network at the CR and its function, we used a biochemical approach coupled to proteomics to identify additional proteins (Rgf3, Art1, Spa2, and Pos1) that are integrated into this network. Cell biological and genetic analyses of these SH3 partners implicate them in a range of activities that ensure the fidelity of cell division, including promoting cell wall metabolism and influencing cell morphogenesis.
© 2015 Ren et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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21 MeSH Terms
LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer.
Schwarz LJ, Fox EM, Balko JM, Garrett JT, Kuba MG, Estrada MV, González-Angulo AM, Mills GB, Red-Brewer M, Mayer IA, Abramson V, Rizzo M, Kelley MC, Meszoely IM, Arteaga CL
(2014) J Clin Invest 124: 5490-502
MeSH Terms: Amino Acid Substitution, Aminopyridines, Animals, Breast Neoplasms, Dasatinib, Drug Resistance, Neoplasm, Drug Synergism, Estrogen Receptor Modulators, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Nude, Morpholines, Mutation, Missense, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Protein Kinase Inhibitors, Pyrimidines, Receptors, Estrogen, Thiazoles, Xenograft Model Antitumor Assays, src Homology Domains, src-Family Kinases
Show Abstract · Added February 16, 2016
Estrogen receptor-positive (ER(+)) breast cancers adapt to hormone deprivation and become resistant to antiestrogen therapy. Here, we performed deep sequencing on ER(+) tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole and identified a D189Y mutation in the inhibitory SH2 domain of the SRC family kinase (SFK) LYN. Evaluation of 463 breast tumors in The Cancer Genome Atlas revealed four LYN mutations, two of which affected the SH2 domain. In addition, LYN was upregulated in multiple ER(+) breast cancer lines resistant to long-term estrogen deprivation (LTED). An RNAi-based kinome screen revealed that LYN is required for growth of ER(+) LTED breast cancer cells. Kinase assays and immunoblot analyses of SRC substrates in transfected cells indicated that LYN(D189Y) has higher catalytic activity than WT protein. Further, LYN(D189Y) exhibited reduced phosphorylation at the inhibitory Y507 site compared with LYN(WT). Other SH2 domain LYN mutants, E159K and K209N, also exhibited higher catalytic activity and reduced inhibitory site phosphorylation. LYN(D189Y) overexpression abrogated growth inhibition by fulvestrant and/or the PI3K inhibitor BKM120 in 3 ER(+) breast cancer cell lines. The SFK inhibitor dasatinib enhanced the antitumor effect of BKM120 and fulvestrant against estrogen-deprived ER(+) xenografts but not LYN(D189Y)-expressing xenografts. These results suggest that LYN mutations mediate escape from antiestrogens in a subset of ER(+) breast cancers.
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26 MeSH Terms
Tyrosine phosphorylation within the SH3 domain regulates CAS subcellular localization, cell migration, and invasiveness.
Janoštiak R, Tolde O, Brůhová Z, Novotný M, Hanks SK, Rösel D, Brábek J
(2011) Mol Biol Cell 22: 4256-67
MeSH Terms: Animals, Cell Adhesion Molecules, Cell Line, Transformed, Cell Line, Tumor, Cell Movement, Cell Transformation, Neoplastic, Crk-Associated Substrate Protein, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesions, Green Fluorescent Proteins, Humans, Mice, Mutation, Neoplasm Invasiveness, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 12, Signal Transduction, Tyrosine, src Homology Domains
Show Abstract · Added January 20, 2015
Crk-associated substrate (CAS) is a major tyrosine-phosphorylated protein in cells transformed by v-crk and v-src oncogenes and plays an important role in invasiveness of Src-transformed cells. A novel phosphorylation site on CAS, Tyr-12 (Y12) within the ligand-binding hydrophobic pocket of the CAS SH3 domain, was identified and found to be enriched in Src-transformed cells and invasive human carcinoma cells. To study the biological significance of CAS Y12 phosphorylation, phosphomimicking Y12E and nonphosphorylatable Y12F mutants of CAS were studied. The phosphomimicking mutation decreased interaction of the CAS SH3 domain with focal adhesion kinase (FAK) and PTP-PEST and reduced tyrosine phosphorylation of FAK. Live-cell imaging showed that green fluorescent protein-tagged CAS Y12E mutant is, in contrast to wild-type or Y12F CAS, excluded from focal adhesions but retains its localization to podosome-type adhesions. Expression of CAS-Y12F in cas-/- mouse embryonic fibroblasts resulted in hyperphosphorylation of the CAS substrate domain, and this was associated with slower turnover of focal adhesions and decreased cell migration. Moreover, expression of CAS Y12F in Src-transformed cells greatly decreased invasiveness when compared to wild-type CAS expression. These findings reveal an important role of CAS Y12 phosphorylation in the regulation of focal adhesion assembly, cell migration, and invasiveness of Src-transformed cells.
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19 MeSH Terms
Cortactin controls cell motility and lamellipodial dynamics by regulating ECM secretion.
Sung BH, Zhu X, Kaverina I, Weaver AM
(2011) Curr Biol 21: 1460-9
MeSH Terms: Actin-Related Protein 2-3 Complex, Actins, Blotting, Western, Cell Line, Cell Membrane, Cell Movement, Cortactin, Extracellular Matrix, Fibronectins, Humans, Microscopy, Fluorescence, Protein Binding, Pseudopodia, src Homology Domains
Show Abstract · Added December 10, 2013
BACKGROUND - Branched actin assembly is critical for both cell motility and membrane trafficking. The branched actin regulator cortactin is generally considered to promote cell migration by controlling leading-edge lamellipodial dynamics. However, recent reports indicate that lamellipodia are not required for cell movement, suggesting an alternate mechanism.
RESULTS - Because cortactin also regulates membrane trafficking and adhesion dynamics, we hypothesized that altered secretion of extracellular matrix (ECM) and/or integrin trafficking might underlie motility defects of cortactin-knockdown (KD) cells. Consistent with a primary defect in ECM secretion, both motility and lamellipodial defects of cortactin-KD cells were fully rescued by plating on increasing concentrations of exogenous ECM. Furthermore, cortactin-KD cell speed defects were rescued on cell-free autocrine ECM produced by control cells, but not on ECM produced by cortactin-KD cells. Investigation of the mechanism revealed that whereas endocytosed fibronectin (FN) is redeposited at the basal cell surface by control cells, cortactin-KD cells exhibit defective FN secretion and abnormal FN retention in a late endocytic/lysosomal compartment. Cortactin-KD motility and FN deposition defects were phenocopied by KD in control cells of the lysosomal fusion regulator synaptotagmin-7. Rescue of cortactin-KD cells by expression of cortactin-binding domain mutants revealed that interaction with the Arp2/3 complex and actin filaments is essential for rescue of both cell motility and autocrine ECM secretion phenotypes, whereas binding of SH3-domain partners is not required.
CONCLUSIONS - Efficient cell motility, promoted by cortactin regulation of branched actin networks, involves processing and resecretion of internalized ECM from a late endosomal/lysosomal compartment.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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14 MeSH Terms
Crk-associated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRC-transformed cells.
Brábek J, Constancio SS, Siesser PF, Shin NY, Pozzi A, Hanks SK
(2005) Mol Cancer Res 3: 307-15
MeSH Terms: Animals, Binding Sites, Cell Line, Transformed, Cell Movement, Cells, Cultured, Collagen, Cytoskeletal Proteins, Drug Combinations, Enzyme Activation, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Genes, src, Injections, Subcutaneous, Laminin, Lung Neoplasms, Matrix Metalloproteinase 2, Mice, Mice, Nude, Neoplasm Invasiveness, Neoplasm Transplantation, Oncogene Protein v-crk, Paxillin, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Proteoglycans, Retroviridae Proteins, Oncogenic, Tyrosine, src Homology Domains
Show Abstract · Added February 24, 2014
Crk-associated substrate (CAS, p130Cas) is a major tyrosine phosphorylated protein in cells transformed by v-crk and v-src oncogenes. We recently reported that reexpression of CAS in CAS-deficient mouse embryo fibroblasts transformed by oncogenic Src promoted an invasive phenotype associated with enhanced cell migration through Matrigel, organization of actin into large podosome ring and belt structures, activation of matrix metalloproteinase-2, and elevated tyrosine phosphorylation of the focal adhesion proteins FAK and paxillin. We have now extended these studies to examine the mechanism by which CAS achieves these changes and to evaluate the potential role for CAS in promoting in vivo tumor growth and metastasis. Whereas the presence or absence of CAS did not alter the primary growth of subcutaneous-injected Src-transformed mouse embryo fibroblasts, CAS expression was required to promote lung metastasis following removal of the primary tumor. The substrate domain YxxP tyrosines, the major sites of CAS phosphorylation by Src that mediate interactions with Crk, were found to be critical for promoting both invasive and metastatic properties of the cells. The ability of CAS to promote Matrigel invasion, formation of large podosome structures, and tyrosine phosphorylation of Src substrates, including FAK, paxillin, and cortactin, was also strictly dependent on the YxxP tyrosines. In contrast, matrix metalloproteinase-2 activation was most dependent on the CAS SH3 domain, whereas the substrate domain YxxP sites also contributed to this property. Thus multiple CAS-mediated signaling events are implicated in promoting invasive and metastatic properties of Src-transformed cells.
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29 MeSH Terms
Tea4p links microtubule plus ends with the formin for3p in the establishment of cell polarity.
Martin SG, McDonald WH, Yates JR, Chang F
(2005) Dev Cell 8: 479-91
MeSH Terms: Actins, Amino Acid Sequence, Cell Cycle Proteins, Cell Polarity, Cytoskeleton, Formins, Microtubule-Associated Proteins, Microtubules, Molecular Sequence Data, Multiprotein Complexes, Recombinant Fusion Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Sequence Alignment, Two-Hybrid System Techniques, src Homology Domains
Show Abstract · Added March 20, 2014
Microtubules regulate actin-based processes such as cell migration and cytokinesis, but molecular mechanisms are not understood. In the fission yeast Schizosaccharomyces pombe, microtubule plus ends regulate cell polarity in part by transporting the kelch repeat protein tea1p to cell ends. Here, we identify tea4p, a SH3 domain protein that binds directly to tea1p. Like tea1p, tea4p localizes to growing microtubule plus ends and to cortical sites at cell ends, and it is necessary for the establishment of bipolar growth. Tea4p binds directly to and recruits the formin for3p, which nucleates actin cable assembly. During "new end take off" (NETO), formation of a protein complex that includes tea1p, tea4p, and for3p is necessary and sufficient for the establishment of cell polarity and localized actin assembly at new cell ends. Our results suggest a molecular mechanism for how microtubule plus ends regulate the spatial distribution of actin assembly.
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16 MeSH Terms
Fgd1, the Cdc42 GEF responsible for Faciogenital Dysplasia, directly interacts with cortactin and mAbp1 to modulate cell shape.
Hou P, Estrada L, Kinley AW, Parsons JT, Vojtek AB, Gorski JL
(2003) Hum Mol Genet 12: 1981-93
MeSH Terms: Actin Cytoskeleton, Actin-Related Protein 2, Actin-Related Protein 3, Amino Acid Sequence, Animals, Cell Line, Cell Size, Cortactin, Cytoskeletal Proteins, Facial Bones, Fibrous Dysplasia, Polyostotic, Guanine Nucleotide Exchange Factors, Mice, Microfilament Proteins, Molecular Sequence Data, Proteins, Sequence Homology, Amino Acid, Syndrome, Urogenital Abnormalities, cdc42 GTP-Binding Protein, src Homology Domains
Show Abstract · Added February 27, 2013
FGD1 mutations result in Faciogenital Dysplasia (FGDY), an X-linked human disease that affects skeletal formation and embryonic morphogenesis. FGD1 and Fgd1, the mouse FGD1 ortholog, encode guanine nucleotide exchange factors (GEF) that specifically activate Cdc42, a Rho GTPase that controls the organization of the actin cytoskeleton. To further understand FGD1/Fgd1 signaling and begin to elucidate the molecular pathophysiology of FGDY, we demonstrate that Fgd1 directly interacts with cortactin and mouse actin-binding protein 1 (mAbp1), actin-binding proteins that regulate actin polymerization through the Arp2/3 complex. In yeast two-hybrid studies, cortactin and mAbp1 Src homology 3 (SH3) domains interact with a single Fgd1 SH3-binding domain (SH3-BD), and biochemical studies show that the Fgd1 SH3-BD directly binds to cortactin and mAbp1 in vitro. Immunoprecipitation studies show that Fgd1 interacts with cortactin and mAbp1 in vivo and that Fgd1 SH3-BD mutations disrupt binding. Immunocytochemical studies show that Fgd1 colocalizes with cortactin and mAbp1 in lamellipodia and membrane ruffles, and that Fgd1 subcellular targeting is dynamic. By using truncated cortactin proteins, immunocytochemical studies show that the cortactin SH3 domain targets Fgd1 to the subcortical actin cytoskeleton, and that abnormal Fgd1 localization results in actin cytoskeletal abnormalities and significant changes in cell shape and viability. Thus, this study provides novel in vitro and in vivo evidence that Fgd1 specifically and directly interacts with cortactin and mAbp1, and that these interactions play an important role in regulating the actin cytoskeleton and, subsequently, cell shape.
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21 MeSH Terms
Interleukin-4 and interleukin-13 signaling connections maps.
Kelly-Welch AE, Hanson EM, Boothby MR, Keegan AD
(2003) Science 300: 1527-8
MeSH Terms: Amino Acid Motifs, Animals, Asthma, Humans, Hypersensitivity, Interleukin-13, Interleukin-13 Receptor alpha1 Subunit, Interleukin-4, Lymphocyte Activation, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Phosphotyrosine, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, Receptors, Interleukin, Receptors, Interleukin-13, Receptors, Interleukin-4, STAT6 Transcription Factor, Signal Transduction, T-Lymphocytes, Trans-Activators, src Homology Domains
Show Abstract · Added December 10, 2013
Cytokines are inflammatory mediators important in responding to pathogens and other foreign challenges. Interleukin-4 (IL-4) and IL-13 are two cytokines produced by T helper type 2 cells, mast cells, and basophils. In addition to their physiological roles, these cytokines are also implicated in pathological conditions such as asthma and allergy. IL-4 can stimulate two receptors, type I and type II, whereas IL-13 signaling is mediated only by the type II receptor (see the STKE Connections Maps). These cytokines activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascades, which may contribute to allergic responses. In addition, stimulation of the phosphatidylinositol 3-kinase (PI3K) pathway through recruitment of members of the insulin receptor substrate family may contribute to survival and proliferation.
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24 MeSH Terms
Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation.
Weaver AM, Karginov AV, Kinley AW, Weed SA, Li Y, Parsons JT, Cooper JA
(2001) Curr Biol 11: 370-4
MeSH Terms: Actin Cytoskeleton, Actin-Related Protein 2, Actin-Related Protein 3, Actins, Animals, Binding Sites, Cattle, Cortactin, Cytoskeletal Proteins, Microfilament Proteins, Nerve Tissue Proteins, Recombinant Fusion Proteins, Wiskott-Aldrich Syndrome Protein, Neuronal, src Homology Domains
Show Abstract · Added March 5, 2014
Cortactin is a c-src substrate associated with sites of dynamic actin assembly at the leading edge of migrating cells. We previously showed that cortactin binds to Arp2/3 complex, the essential molecular machine for nucleating actin filament assembly. In this study, we demonstrate that cortactin activates Arp2/3 complex based on direct visualization of filament networks and pyrene actin assays. Strikingly, cortactin potently inhibited the debranching of filament networks. When cortactin was added in combination with the active VCA fragment of N-WASp, they synergistically enhanced Arp2/3-induced actin filament branching. The N-terminal acidic and F-actin binding domains of cortactin were both necessary to activate Arp2/3 complex. These results support a model in which cortactin modulates actin filament dendritic nucleation by two mechanisms, (1) direct activation of Arp2/3 complex and (2) stabilization of newly generated filament branch points. By these mechanisms, cortactin may promote the formation and stabilization of the actin network that drives protrusion at the leading edge of migrating cells.
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14 MeSH Terms