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  1. Article ; Online: Lysine Acetylation Reshapes the Downstream Signaling Landscape of Vav1 in Lymphocytes.

    Rodríguez-Fdez, Sonia / Fernández-Nevado, Lucía / Lorenzo-Martín, L Francisco / Bustelo, Xosé R

    Cells

    2020  Volume 9, Issue 3

    Abstract: Vav1 works both as a catalytic Rho GTPase activator and an adaptor molecule. These functions, which are critical for T cell development and antigenic responses, are tyrosine phosphorylation-dependent. However, it is not known whether other ... ...

    Abstract Vav1 works both as a catalytic Rho GTPase activator and an adaptor molecule. These functions, which are critical for T cell development and antigenic responses, are tyrosine phosphorylation-dependent. However, it is not known whether other posttranslational modifications can contribute to the regulation of the biological activity of this protein. Here, we show that Vav1 becomes acetylated on lysine residues in a stimulation- and SH2 domain-dependent manner. Using a collection of both acetylation- and deacetylation-mimicking mutants, we show that the acetylation of four lysine residues (Lys
    MeSH term(s) Acetylation ; Animals ; COS Cells ; Chlorocebus aethiops ; Humans ; Jurkat Cells ; Lysine/metabolism ; NFATC Transcription Factors/metabolism ; Phosphorylation ; Protein Binding/physiology ; Protein Processing, Post-Translational/physiology ; Proto-Oncogene Proteins c-vav/metabolism ; Signal Transduction/physiology
    Chemical Substances NFATC Transcription Factors ; Proto-Oncogene Proteins c-vav ; VAV1 protein, human ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2020-03-04
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9030609
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model.

    Robles-Valero, Javier / Fernández-Nevado, Lucía / Cuadrado, Myriam / Lorenzo-Martín, Luis Francisco / Fernández-Pisonero, Isabel / Abad, Antonio / Redín, Esther / Montuenga, Luis / Martín-Zanca, Dionisio / Bigas, Anna / Mallo, Moisés / Dosil, Mercedes / Bustelo, Xosé R

    Molecular oncology

    2022  Volume 16, Issue 19, Page(s) 3533–3553

    Abstract: Mutations in the VAV1 guanine nucleotide exchange factor 1 have been recently found in peripheral T cell lymphoma and nonsmall-cell lung cancer (NSCLC). To understand their pathogenic potential, we generated a gene-edited mouse model that expresses a ... ...

    Abstract Mutations in the VAV1 guanine nucleotide exchange factor 1 have been recently found in peripheral T cell lymphoma and nonsmall-cell lung cancer (NSCLC). To understand their pathogenic potential, we generated a gene-edited mouse model that expresses a VAV1 mutant protein that recapitulates the signalling alterations present in the VAV1 mutant subclass most frequently found in tumours. We could not detect any overt tumourigenic process in those mice. However, the concurrent elimination of the Trp53 tumour suppressor gene in them drives T cell lymphomagenesis. This process represents an exacerbation of the normal functions that wild-type VAV1 plays in follicular helper T cells. We also found that, in combination with the Kras oncogene, the VAV1 mutant version favours progression of NSCLC. These data indicate that VAV1 mutations play critical, although highly cell-type-specific, roles in tumourigenesis. They also indicate that such functions are contingent on the mutational landscape of the tumours involved.
    MeSH term(s) Animals ; Gene Editing ; Mice ; Mutant Proteins/metabolism ; Mutation/genetics ; Neoplasms ; Proto-Oncogene Proteins c-vav/genetics ; Proto-Oncogene Proteins c-vav/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism
    Chemical Substances Mutant Proteins ; Proto-Oncogene Proteins c-vav ; Vav1 protein, mouse ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
    Language English
    Publishing date 2022-08-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2415106-3
    ISSN 1878-0261 ; 1574-7891
    ISSN (online) 1878-0261
    ISSN 1574-7891
    DOI 10.1002/1878-0261.13295
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6637: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis.

    Robles-Valero, Javier / Fernández-Nevado, Lucía / Lorenzo-Martín, L Francisco / Cuadrado, Myriam / Fernández-Pisonero, Isabel / Rodríguez-Fdez, Sonia / Astorga-Simón, Elsa N / Abad, Antonio / Caloto, Rubén / Bustelo, Xosé R

    The EMBO journal

    2021  Volume 40, Issue 22, Page(s) e108125

    Abstract: Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T-cell lymphoma (PTCL), non-small cell lung cancer, and other tumors. However, their pathobiological significance ...

    Abstract Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T-cell lymphoma (PTCL), non-small cell lung cancer, and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer-associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional impact on the three main VAV1 signaling branches, GEF-dependent activation of RAC1, GEF-independent adaptor-like, and tumor suppressor functions. These mutations target new and previously established regulatory layers of the protein, leading to quantitative and qualitative changes in VAV1 signaling output. We also demonstrate that the most frequent VAV1 mutant subtype drives PTCL formation in mice. This process requires the concurrent engagement of two downstream signaling branches that promote the chronic activation and transformation of follicular helper T cells. Collectively, these data reveal the genetic constraints associated with the lymphomagenic potential of VAV1 mutant subsets, similarities with other PTCL driver genes, and potential therapeutic vulnerabilities.
    MeSH term(s) Animals ; CD4-Positive T-Lymphocytes/pathology ; CD4-Positive T-Lymphocytes/physiology ; CD4-Positive T-Lymphocytes/transplantation ; COS Cells ; Cell Proliferation/genetics ; Chlorocebus aethiops ; Humans ; Jurkat Cells ; Lymphoma, T-Cell, Peripheral/genetics ; Lymphoma, T-Cell, Peripheral/pathology ; Mice, Transgenic ; Mutation ; Proto-Oncogene Proteins c-vav/chemistry ; Proto-Oncogene Proteins c-vav/genetics ; Proto-Oncogene Proteins c-vav/metabolism ; Signal Transduction ; rac1 GTP-Binding Protein/genetics ; rac1 GTP-Binding Protein/metabolism
    Chemical Substances Proto-Oncogene Proteins c-vav ; RAC1 protein, human ; VAV1 protein, human ; Vav1 protein, mouse ; rac1 GTP-Binding Protein (EC 3.6.5.2)
    Language English
    Publishing date 2021-10-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.15252/embj.2021108125
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1808: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 100: Show issues

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  4. Article ; Online: The multikinase inhibitor EC-70124 synergistically increased the antitumor activity of doxorubicin in sarcomas.

    Estupiñan, Oscar / Santos, Laura / Rodriguez, Aida / Fernandez-Nevado, Lucia / Costales, Paula / Perez-Escuredo, Jhudit / Hermosilla, Maria Ana / Oro, Patricia / Rey, Veronica / Tornin, Juan / Allonca, Eva / Fernandez-Garcia, Maria Teresa / Alvarez-Fernandez, Carlos / Braña, Alejandro / Astudillo, Aurora / Menendez, Sofia T / Moris, Francisco / Rodriguez, Rene

    International journal of cancer

    2019  Volume 145, Issue 1, Page(s) 254–266

    Abstract: Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an ... ...

    Abstract Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro-tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro-tumoral kinases. Therefore, we studied the antitumor activity of EC-70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro-survival kinases. Evaluation of the phospho-kinase profile in cell-of-origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC-70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC-70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC-70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC-70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatments.
    MeSH term(s) ATP-Binding Cassette Transporters/antagonists & inhibitors ; ATP-Binding Cassette Transporters/metabolism ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Carbazoles/pharmacology ; Doxorubicin/administration & dosage ; Doxorubicin/pharmacology ; Drug Synergism ; Female ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/pharmacology ; Sarcoma/drug therapy ; Sarcoma/enzymology ; Signal Transduction/drug effects ; Staurosporine/analogs & derivatives ; Staurosporine/pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    Chemical Substances ATP-Binding Cassette Transporters ; Carbazoles ; Protein Kinase Inhibitors ; Doxorubicin (80168379AG) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Staurosporine (H88EPA0A3N) ; midostaurin (ID912S5VON)
    Language English
    Publishing date 2019-01-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.32081
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 478: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 576: Show issues

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  5. Article ; Online: FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway.

    Tornin, Juan / Hermida-Prado, Francisco / Padda, Ranjit Singh / Gonzalez, M Victoria / Alvarez-Fernandez, Carlos / Rey, Veronica / Martinez-Cruzado, Lucia / Estupiñan, Oscar / Menendez, Sofia T / Fernandez-Nevado, Lucia / Astudillo, Aurora / Rodrigo, Juan P / Lucien, Fabrice / Kim, Yohan / Leong, Hon S / Garcia-Pedrero, Juana Maria / Rodriguez, Rene

    Neoplasia (New York, N.Y.)

    2017  Volume 20, Issue 1, Page(s) 44–56

    Abstract: Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one ... ...

    Abstract Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP-mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP-expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP-mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatment.
    MeSH term(s) Acute-Phase Proteins/metabolism ; Focal Adhesion Kinase 1/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Liposarcoma, Myxoid/genetics ; Liposarcoma, Myxoid/metabolism ; Liposarcoma, Myxoid/pathology ; Neoplastic Stem Cells/metabolism ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; RNA, Small Interfering/genetics ; RNA-Binding Protein FUS/genetics ; RNA-Binding Protein FUS/metabolism ; Signal Transduction ; Transcription Factor CHOP/genetics ; Transcription Factor CHOP/metabolism ; rho-Associated Kinases/metabolism ; src-Family Kinases/metabolism
    Chemical Substances Acute-Phase Proteins ; Oncogene Proteins, Fusion ; RNA, Small Interfering ; RNA-Binding Protein FUS ; TLS-CHOP fusion protein, human ; acute-phase protein rho ; Transcription Factor CHOP (147336-12-7) ; Focal Adhesion Kinase 1 (EC 2.7.10.2) ; PTK2 protein, human (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2) ; rho-Associated Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2017-11-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1483840-0
    ISSN 1476-5586 ; 1522-8002
    ISSN (online) 1476-5586
    ISSN 1522-8002
    DOI 10.1016/j.neo.2017.11.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5203: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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