TY - JOUR A1 - Butt, Elke A1 - Howard, Cory M. A1 - Raman, Dayanidhi T1 - LASP1 in cellular signaling and gene expression: more than just a cytoskeletal regulator JF - Cells N2 - 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. KW - LASP1 KW - AKT KW - CXCR4 KW - structure KW - cytoskeleton KW - phosphorylation KW - transcriptional regulation KW - epigenetics KW - nucleus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297447 SN - 2073-4409 VL - 11 IS - 23 ER - TY - JOUR A1 - Butt, Elke A1 - Stempfle, Katrin A1 - Lister, Lorenz A1 - Wolf, Felix A1 - Kraft, Marcella A1 - Herrmann, Andreas B. A1 - Viciano, Cristina Perpina A1 - Weber, Christian A1 - Hochhaus, Andreas A1 - Ernst, Thomas A1 - Hoffmann, Carsten A1 - Zernecke, Alma A1 - Frietsch, Jochen J. T1 - Phosphorylation-dependent differences in CXCR4-LASP1-AKT1 interaction between breast cancer and chronic myeloid leukemia JF - Cells N2 - 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. KW - LASP1 KW - CXCR4 KW - AKT1 KW - CML KW - breast cancer Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200638 SN - 2073-4409 VL - 9 IS - 2 ER - TY - JOUR A1 - Endres, Marcel A1 - Kneitz, Susanne A1 - Orth, Martin F. A1 - Perera, Ruwan K. A1 - Zernecke, Alma A1 - Butt, Elke T1 - Regulation of matrix metalloproteinases (MMPs) expression and secretion in MDA-MB-231 breast cancer cells by LIM and SH3 protein 1 (LASP1) JF - Oncotarget N2 - 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. KW - LASP1 KW - c-Fos KW - extracellular matrix KW - AP-1 KW - matrix metalloproteinases KW - breast cancer Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176920 VL - 7 IS - 39 ER - TY - JOUR A1 - Frietsch, Jochen J. A1 - Kastner, Carolin A1 - Grunewald, Thomas G.P. A1 - Schweigel, Hardy A1 - Nollau, Peter A1 - Ziermann, Janine A1 - Clement, Joachim H. A1 - La Resée, Paul A1 - Hochhaus, Andreas A1 - Butt, Elke T1 - LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia JF - Oncotarget N2 - 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. KW - CRKL KW - nilotinib KW - BCR-ABL KW - CML KW - LASP1 Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120639 SN - 1949-2553 VL - 5 IS - 14 ER - TY - JOUR A1 - Gil-Pulido, Jesus A1 - Cochain, Clement A1 - Lippert, Malte A. A1 - Schneider, Nicole A1 - Butt, Elke A1 - Amézaga, Núria A1 - Zernecke, Alma T1 - Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice JF - PLoS ONE N2 - Atherosclerosis is the main underlying cause for cardiovascular events such as myocardial infarction and stroke and its development might be influenced by immune cells. Dendritic cells (DCs) bridge innate and adaptive immune responses by presenting antigens to T cells and releasing a variety of cytokines. Several subsets of DCs can be discriminated that engage specific transcriptional pathways for their development. Basic leucine zipper transcription factor ATF-like 3 (Batf3) is required for the development of classical CD8α\(^{+}\) and CD103\(^{+}\) DCs. By crossing mice deficient in Batf3 with atherosclerosis-prone low density lipoprotein receptor (Ldlr\(^{−/-}\))-deficient mice we here aimed to further address the contribution of Batf3-dependent CD8α\(^{+}\) and CD103\(^{+}\) antigen-presenting cells to atherosclerosis. We demonstrate that deficiency in Batf3 entailed mild effects on the immune response in the spleen but did not alter atherosclerotic lesion formation in the aorta or aortic root, nor affected plaque phenotype in low density lipoprotein receptor-deficient mice fed a high fat diet. We thus provide evidence that Batf3-dependent antigen-presenting cells do not have a prominent role in atherosclerosis. KW - atherosclerosis KW - dendritic cells KW - Batf3 KW - deficiency Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170535 VL - 12 IS - 8 ER - TY - JOUR A1 - Hailer, Amelie A1 - Grunewald, Thomas G. P. A1 - Orth, Martin A1 - Reiss, Cora A1 - Kneitz, Burkhard A1 - Spahn, Martin A1 - Butt, Elke T1 - 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 JF - Oncotarget N2 - 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. KW - mir-203 KW - PSA KW - LNCaP KW - LASP1 KW - prostate cancer Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120540 SN - 1949-2553 VL - 5 IS - 12 ER - TY - JOUR A1 - Herrmann, Andreas B. A1 - Müller, Martha‐Lena A1 - Orth, Martin F. A1 - Müller, Jörg P. A1 - Zernecke, Alma A1 - Hochhaus, Andreas A1 - Ernst, Thomas A1 - Butt, Elke A1 - Frietsch, Jochen J. T1 - Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance JF - Journal of Cellular and Molecular Medicine N2 - 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. KW - BCR‐ABL KW - CML KW - CXCR4 KW - LASP1 KW - nilotinib KW - precursor cells Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214122 VL - 24 IS - 5 SP - 2942 EP - 2955 ER - TY - JOUR A1 - Israel, Ina A1 - Riehl, Gabriele A1 - Butt, Elke A1 - Buck, Andreas K. A1 - Samnick, Samuel T1 - Gallium-68-labeled KISS1-54 peptide for mapping KISS1 receptor via PET: initial evaluation in human tumor cell lines and in tumor-bearing mice JF - Pharmaceuticals N2 - Kisspeptins (KPs, KISS1) and their receptor (KISS1R) play a pivotal role as metastasis suppressor for many cancers. Low or lost KP expression is associated with higher tumor grade, increased metastatic potential, and poor prognosis. Therefore, KP expression has prognostic relevance and correlates with invasiveness in cancers. Furthermore, KISS1R represents a very promising target for molecular imaging and therapy for KISS1R-expressing tumors. The goal of this study was to evaluate the developed KISS1-54 derivative, [\(^{68}\)Ga]KISS1-54, as a PET-imaging probe for KISS1R-expressing tumors. The NODAGA-KISS1-54 peptide was labeled by Gallium-68, and the stability of the resulting [\(^{68}\)Ga]KISS1-54 evaluated in injection solution and human serum, followed by an examination in different KISS1R-expressing tumor cell lines, including HepG2, HeLa, MDA-MB-231, MCF7, LNCap, SK-BR-3, and HCT116. Finally, [\(^{68}\)Ga]KISS1-54 was tested in LNCap- and MDA-MB-231-bearing mice, using µ-PET, assessing its potential as an imaging probe for PET. [\(^{68}\)Ga]KISS1-54 was obtained in a 77 ± 7% radiochemical yield and at a >99% purity. The [\(^{68}\)Ga]KISS1-54 cell uptake amounted to 0.6–4.4% per 100,000 cells. Moreover, the accumulation of [\(^{68}\)Ga]KISS1-54 was effectively inhibited by nonradioactive KISS1-54. In [\(^{68}\)Ga]KISS1-54-PET, KISS1R-positive LNCap-tumors were clearly visualized as compared to MDA-MB-231-tumor implant with predominantly intracellular KISS1R expression. Our first results suggest that [\(^{68}\)Ga]KISS1-54 is a promising candidate for a radiotracer for targeting KISS1R-expressing tumors via PET. KW - [\(^{68}\)]KISS1-54 KW - KISS1 receptor KW - GPR54 KW - kisspeptin KW - human tumor cell lines KW - positron emission tomography KW - PET KW - KISS1-54 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-355898 SN - 1424-8247 VL - 17 IS - 1 ER - TY - JOUR A1 - Lepa, Carolin A1 - Möller‐Kerutt, Annika A1 - Stölting, Miriam A1 - Picciotto, Cara A1 - Eddy, Mee‐Ling A1 - Butt, Elke A1 - Kerjaschki, Dontscho A1 - Korb‐Pap, Adelheid A1 - Vollenbröker, Beate A1 - Weide, Thomas A1 - George, Britta A1 - Kremerskothen, Joachim A1 - Pavenstädt, Hermann T1 - LIM and SH3 protein 1 (LASP‐1): A novel link between the slit membrane and actin cytoskeleton dynamics in podocytes JF - The FASEB Journal N2 - The foot processes of podocytes exhibit a dynamic actin cytoskeleton, which maintains their complex cell structure and antagonizes the elastic forces of the glomerular capillary. Interdigitating secondary foot processes form a highly selective filter for proteins in the kidney, the slit membrane. Knockdown of slit membrane components such as Nephrin or Neph1 and cytoskeletal adaptor proteins such as CD2AP in mice leads to breakdown of the filtration barrier with foot process effacement, proteinuria, and early death of the mice. Less is known about the crosstalk between the slit membrane‐associated proteins and cytoskeletal components inside the podocyte foot processes. Our study shows that LASP‐1, an actin‐binding protein, is highly expressed in podocytes. Electron microscopy studies demonstrate that LASP‐1 is found at the slit membrane suggesting a role in anchoring slit membrane components to the actin cytoskeleton. Live cell imaging experiments with transfected podocytes reveal that LASP‐1 is either part of a highly dynamic granular complex or a static, actin cytoskeleton‐bound protein. We identify CD2AP as a novel LASP‐1 binding partner that regulates its association with the actin cytoskeleton. Activation of the renin‐angiotensin‐aldosterone system, which is crucial for podocyte function, leads to phosphorylation and altered localization of LASP‐1. In vivo studies using the Drosophila nephrocyte model indicate that Lasp is necessary for the slit membrane integrity and functional filtration. KW - actin cytoskeleton KW - angiotensin KW - CD2AP KW - nephrocyte KW - slit membrane Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215522 VL - 34 IS - 4 SP - 5453 EP - 5464 ER - TY - JOUR A1 - Orth, Martin F. A1 - Cazes, Alex A1 - Butt, Elke A1 - Grunewald, Thomas G. P. T1 - An update on the LIM and SH3 domain protein 1 (LASP1): a versatile structural, signaling, and biomarker protein JF - Oncotarget N2 - 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. KW - LASP1 KW - cancer KW - biomarker KW - microRNA KW - nucleo-cytoplasmic Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144546 VL - 6 IS - 1 ER -