@article{ButtHowardRaman2022,
  author    = {Butt, Elke and Howard, Cory M. and Raman, Dayanidhi},
  title     = {LASP1 in cellular signaling and gene expression: more than just a cytoskeletal regulator},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {23},
  issn      = {2073-4409},
  doi       = {10.3390/cells11233817},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297447},
  year      = {2022},
  abstract  = {LIM and SH3 protein 1 was originally identified as a structural cytoskeletal protein with scaffolding function. However, recent data suggest additional roles in cell signaling and gene expression, especially in tumor cells. These novel functions are primarily regulated by the site-specific phosphorylation of LASP1. This review will focus on specific phosphorylation-dependent interaction between LASP1 and cellular proteins that orchestrate primary tumor progression and metastasis. More specifically, we will describe the role of LASP1 in chemokine receptor, and PI3K/AKT signaling. We outline the nuclear role for LASP1 in terms of epigenetics and transcriptional regulation and modulation of oncogenic mRNA translation. Finally, newly identified roles for the cytoskeletal function of LASP1 next to its known canonical F-actin binding properties are included.},
  language  = {en}
}
@article{ButtStempfleListeretal.2020,
  author    = {Butt, Elke and Stempfle, Katrin and Lister, Lorenz and Wolf, Felix and Kraft, Marcella and Herrmann, Andreas B. and Viciano, Cristina Perpina and Weber, Christian and Hochhaus, Andreas and Ernst, Thomas and Hoffmann, Carsten and Zernecke, Alma and Frietsch, Jochen J.},
  title     = {Phosphorylation-dependent differences in CXCR4-LASP1-AKT1 interaction between breast cancer and chronic myeloid leukemia},
  series = {Cells},
  volume    = {9},
  journal   = {Cells},
  number    = {2},
  issn      = {2073-4409},
  doi       = {10.3390/cells9020444},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200638},
  year      = {2020},
  abstract  = {The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.},
  language  = {en}
}
@article{EndresKneitzOrthetal.2016,
  author    = {Endres, Marcel and Kneitz, Susanne and Orth, Martin F. and Perera, Ruwan K. and Zernecke, Alma and Butt, Elke},
  title     = {Regulation of matrix metalloproteinases (MMPs) expression and secretion in MDA-MB-231 breast cancer cells by LIM and SH3 protein 1 (LASP1)},
  series = {Oncotarget},
  volume    = {7},
  journal   = {Oncotarget},
  number    = {39},
  doi       = {10.18632/oncotarget.11720},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176920},
  pages     = {64244-64259},
  year      = {2016},
  abstract  = {The process of tumor invasion requires degradation of extracellular matrix by proteolytic enzymes. Cancer cells form protrusive invadopodia, which produce and release matrix metalloproteinases (MMPs) to degrade the basement membrane thereby enabling metastasis. We investigated the effect of LASP1, a newly identified protein in invadopodia, on expression, secretion and activation of MMPs in invasive breast tumor cell lines. By analyzing microarray data of in-house generated control and LASP1-depleted MDA-MB-231 breast cancer cells, we observed downregulation of MMP1, -3 and -9 upon LASP1 depletion. This was confirmed by Western blot analysis. Conversely, rescue experiments restored in part MMP expression and secretion. The regulatory effect of LASP1 on MMP expression was also observed in BT-20 breast cancer cells as well as in prostate and bladder cancer cell lines. In line with bioinformatic FunRich analysis of our data, which mapped a high regulation of transcription factors by LASP1, public microarray data analysis detected a correlation between high LASP1 expression and enhanced c-Fos levels, a protein that is part of the transcription factor AP-1 and known to regulate MMP expression. Compatibly, in luciferase reporter assays, AP-1 showed a decreased transcriptional activity after LASP1 knockdown. Zymography assays and Western blot analysis revealed an additional promotion of MMP secretion into the extracellular matrix by LASP1, thus, most likely, altering the microenvironment during cancer progression. The newly identified role of LASP1 in regulating matrix degradation by affecting MMP transcription and secretion elucidated the migratory potential of LASP1 overexpressing aggressive tumor cells in earlier studies.},
  language  = {en}
}
@article{FrietschKastnerGrunewaldetal.2014,
  author    = {Frietsch, Jochen J. and Kastner, Carolin and Grunewald, Thomas G.P. and Schweigel, Hardy and Nollau, Peter and Ziermann, Janine and Clement, Joachim H. and La Res{\´e}e, Paul and Hochhaus, Andreas and Butt, Elke},
  title     = {LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia},
  series = {Oncotarget},
  volume    = {5},
  journal   = {Oncotarget},
  number    = {14},
  issn      = {1949-2553},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120639},
  pages     = {5257-71},
  year      = {2014},
  abstract  = {Chronic myeloid leukemia (CML) is characterized by a genomic translocation generating a permanently active BCR-ABL oncogene with a complex pattern of atypically tyrosine-phosphorylated proteins that drive the malignant phenotype of CML. Recently, the LIM and SH3 domain protein 1 (LASP1) was identified as a component of a six gene signature that is strongly predictive for disease progression and relapse in CML patients. However, the underlying mechanisms why LASP1 expression correlates with dismal outcome remained unresolved. Here, we identified LASP1 as a novel and overexpressed direct substrate of BCR-ABL in CML. We demonstrate that LASP1 is specifically phosphorylated by BCR-ABL at tyrosine-171 in CML patients, which is abolished by tyrosine kinase inhibitor therapy. Further studies revealed that LASP1 phosphorylation results in an association with CRKL - another specific BCR-ABL substrate and bona fide biomarker for BCR-ABL activity. pLASP1-Y171 binds to non-phosphorylated CRKL at its SH2 domain. Accordingly, the BCR-ABL-mediated pathophysiological hyper-phosphorylation of LASP1 in CML disrupts normal regulation of CRKL and LASP1, which likely has implications on downstream BCR-ABL signaling. Collectively, our results suggest that LASP1 phosphorylation might serve as an additional candidate biomarker for assessment of BCR-ABL activity and provide a first step toward a molecular understanding of LASP1 function in CML.},
  language  = {en}
}
@article{HailerGrunewaldOrthetal.2014,
  author    = {Hailer, Amelie and Grunewald, Thomas G. P. and Orth, Martin and Reiss, Cora and Kneitz, Burkhard and Spahn, Martin and Butt, Elke},
  title     = {Loss of tumor suppressor mir-203 mediates overexpression of LIM and SH3 Protein 1 (LASP1) in high-risk prostate cancer thereby increasing cell proliferation and migration},
  series = {Oncotarget},
  volume    = {5},
  journal   = {Oncotarget},
  number    = {12},
  issn      = {1949-2553},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120540},
  pages     = {4144-53},
  year      = {2014},
  abstract  = {Several studies have linked overexpression of the LIM and SH3 domain protein 1 (LASP1) to progression of breast, colon, liver, and bladder cancer. However, its expression pattern and role in human prostate cancer (PCa) remained largely undefined. Analysis of published microarray data revealed a significant overexpression of LASP1 in PCa metastases compared to parental primary tumors and normal prostate epithelial cells. Subsequent gene-set enrichment analysis comparing LASP1-high and -low PCa identified an association of LASP1 with genes involved in locomotory behavior and chemokine signaling. These bioinformatic predictions were confirmed in vitro as the inducible short hairpin RNA-mediated LASP1 knockdown impaired migration and proliferation in LNCaP prostate cancer cells. By immunohistochemical staining and semi-quantitative image analysis of whole tissue sections we found an enhanced expression of LASP1 in primary PCa and lymph node metastases over benign prostatic hyperplasia. Strong cytosolic and nuclear LASP1 immunoreactivity correlated with PSA progression. Conversely, qRT-PCR analyses for mir-203, which is a known translational suppressor of LASP1 in matched RNA samples revealed an inverse correlation of LASP1 protein and mir-203 expression. Collectively, our results suggest that loss of mir-203 expression and thus uncontrolled LASP1 overexpression might drive progression of PCa.},
  language  = {en}
}
@article{HerrmannMuellerOrthetal.2020,
  author    = {Herrmann, Andreas B. and M{\"u}ller, Martha-Lena and Orth, Martin F. and M{\"u}ller, J{\"o}rg P. and Zernecke, Alma and Hochhaus, Andreas and Ernst, Thomas and Butt, Elke and Frietsch, Jochen J.},
  title     = {Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance},
  series = {Journal of Cellular and Molecular Medicine},
  volume    = {24},
  journal   = {Journal of Cellular and Molecular Medicine},
  number    = {5},
  doi       = {10.1111/jcmm.14910},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214122},
  pages     = {2942 -- 2955},
  year      = {2020},
  abstract  = {Chronic myeloid leukaemia (CML) is a clonal myeloproliferative stem cell disorder characterized by the constitutively active BCR-ABL tyrosine kinase. The LIM and SH3 domain protein 1 (LASP1) has recently been identified as a novel BCR-ABL substrate and is associated with proliferation, migration, tumorigenesis and chemoresistance in several cancers. Furthermore, LASP1 was shown to bind to the chemokine receptor 4 (CXCR4), thought to be involved in mechanisms of relapse. In order to identify potential LASP1-mediated pathways and related factors that may help to further eradicate minimal residual disease (MRD), the effect of LASP1 on processes involved in progression and maintenance of CML was investigated. The present data indicate that not only overexpression of CXCR4, but also knockout of LASP1 contributes to proliferation, reduced apoptosis and migration as well as increased adhesive potential of K562 CML cells. Furthermore, LASP1 depletion in K562 CML cells leads to decreased cytokine release and reduced NK cell-mediated cytotoxicity towards CML cells. Taken together, these results indicate that in CML, reduced levels of LASP1 alone and in combination with high CXCR4 expression may contribute to TKI resistance.},
  language  = {en}
}
@article{OrthCazesButtetal.2015,
  author    = {Orth, Martin F. and Cazes, Alex and Butt, Elke and Grunewald, Thomas G. P.},
  title     = {An update on the LIM and SH3 domain protein 1 (LASP1): a versatile structural, signaling, and biomarker protein},
  series = {Oncotarget},
  volume    = {6},
  journal   = {Oncotarget},
  number    = {1},
  doi       = {10.18632/oncotarget.3083},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144546},
  pages     = {26-42},
  year      = {2015},
  abstract  = {The gene encoding the LIM and SH3 domain protein (LASP1) was cloned two decades ago from a cDNA library of breast cancer metastases. As the first protein of a class comprising one N-terminal LIM and one C-terminal SH3 domain, LASP1 founded a new LIM-protein subfamily of the nebulin group. Since its discovery LASP1 proved to be an extremely versatile protein because of its exceptional structure allowing interaction with various binding partners, its ubiquitous expression in normal tissues, albeit with distinct expression patterns, and its ability to transmit signals from the cytoplasm into the nucleus. As a result, LASP1 plays key roles in cell structure, physiological processes, and cell signaling. Furthermore, LASP1 overexpression contributes to cancer aggressiveness hinting to a potential value of LASP1 as a cancer biomarker. In this review we summarize published data on structure, regulation, function, and expression pattern of LASP1, with a focus on its role in human cancer and as a biomarker protein. In addition, we provide a comprehensive transcriptome analysis of published microarrays (n=2,780) that illustrates the expression profile of LASP1 in normal tissues and its overexpression in a broad range of human cancer entities.},
  language  = {en}
}
@article{SubramaniyanSridharanHowardetal.2020,
  author    = {Subramaniyan, Boopathi and Sridharan, Sangita and Howard, Cory M. and Tilley, Augustus M.C. and Basuroy, Tupa and Serna, Ivana de la and Butt, Elke and Raman, Dayanidhi},
  title     = {Role of the CXCR4-LASP1 axis in the stabilization of Snail1 in triple-negative breast cancer},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {9},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12092372},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211217},
  year      = {2020},
  abstract  = {The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). The nuclear LASP1 then interacts with Snail1 in triple-negative breast cancer (TNBC) cell lines. In this study, we report that the nuclear accumulation and retention of Snail1 was dependent on an increase in nuclear LASP1 levels driven by active CXCR4. The CXCR4-LASP1 axis may directly regulate the stabilization of nuclear Snail1, by upregulating nuclear levels of pS473-Akt, pS9-GSK-3β, A20, and LSD1. Furthermore, the activation of CXCR4 induced association of LASP1 with Snail1, A20, GSK-3β, and LSD1 endogenously. Thus, nuclear LASP1 may also regulate protein-protein interactions that facilitate the stability of Snail1. Genetic ablation of LASP1 resulted in the mislocalization of nuclear Snail1, loss of the ability of TNBC cells to invade Matrigel and a dysregulated expression of both epithelial and mesenchymal markers, including an increased expression of ALDH1A1, a marker for epithelial breast cancer stem-like cells. Our findings reveal a novel role for the CXCR4-LASP1 axis in facilitating the stability of nuclear localized Snail1.},
  language  = {en}
}