An emerging link between LIM domain proteins and nuclear receptors

Sala, Stefano; Ampè, Christophe

doi:10.1007/s00018-018-2774-3

Cited by 29 publications

(22 citation statements)

References 95 publications

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“…The LIM domain protein family consists of 65 human proteins, characterized by the presence of the LIM domain 9 . The LIM domain, a highly conserved cysteine-rich domain, participates in protein-protein interactions 10 .…”

Section: Introductionmentioning

confidence: 99%

LIMK2 promotes the metastatic progression of triple-negative breast cancer by activating SRPK1

et al. 2020

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Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype and due to the lack of hormone receptors and HER2 expression, TNBC has limited therapeutic options with chemotherapy being the primary choice for systemic therapy. LIM Domain Kinase 2 (LIMK2) is a serine/threonine kinase that plays an important role in the regulation of actin filament dynamics. Here, we show that LIM domain kinase 2 (LIMK2) is overexpressed in TNBC, and short-hairpin RNA (shRNA)-mediated LIMK2 knockdown or its pharmacological inhibition blocks metastatic attributes of TNBC cells. To determine the mechanism by which LIMK2 promotes TNBC metastatic progression, we performed stable isotope labeling by amino acids in cell culture (SILAC) based unbiased large-scale phosphoproteomics analysis. This analysis identified 258 proteins whose phosphorylation was significantly reduced due to LIMK2 inhibition. Among these proteins, we identified SRSF protein kinase 1 (SRPK1), which encodes for a serine/arginine protein kinase specific for the SR (serine/arginine-rich domain) family of splicing factors. We show that LIMK2 inhibition blocked SRPK1 phosphorylation and consequentially its activity. Furthermore, similar to LIMK2, genetic inhibition of SRPK1 by shRNAs or its pharmacological inhibition blocked the metastatic attributes of TNBC cells. Moreover, the pharmacological inhibition of LIMK2 blocked metastatic progression in mice without affecting primary tumor growth. In sum, these results identified LIMK2 as a facilitator of distal TNBC metastasis and a potential target for preventing TNBC metastatic progression.

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Section: Introductionmentioning

confidence: 99%

LIMK2 promotes the metastatic progression of triple-negative breast cancer by activating SRPK1

et al. 2020

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“…Human nuclear receptors (NRs) are ligand-activated transcription factors that participate in several biological processes [5]. In the last years, NRs have been identi ed as master regulators of broad genetic programs in metazoans [6].…”

Section: Introductionmentioning

confidence: 99%

Human Nuclear Receptors (NRs) Genes Have Prognostic Significance in Hepatocellular Carcinoma Patients

Sun

Shen

2020

Preprint

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Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality in the world. Human nuclear receptors (NRs) have been identified to closely related to various cancer. However, the prognostic significance of NRs on HCC patients has not been studied in detail.Method: We downloaded the mRNA profiles and clinical information of 371 HCC patients from TCGA database and analyzed the expression of 48 NRs. The consensus clustering analysis with the mRNA levels of 48 NRs was performed by the "ConsensusClusterPlus". The Univariate cox regression analysis was performed to predict the prognostic significance of NRs on HCC. The risk score was calculated by the prognostic model constructed based on eight optimal NRs which were selected. Then Multivariate Cox regression analysis was performed to determine whether the risk score is an independent prognostic signature. Finally, the nomogram based on multiple independent prognostic factors including risk score and TNM Stage was used to predict the long-term survival of HCC patients.Results: NRs could effectively separate HCC samples with different prognosis. The prognostic model constructed based on the eight optimal NRs (NR1H3, ESR1, NR1I2, NR2C1, NR6A1, PPARD, PPARG and VDR) could effectively predict the prognosis of HCC patients as an independent prognostic signature. Moreover, the nomogram was constructed based on multiple independent prognostic factors including risk score and TNM Stage and could better predict the long-term survival for 3- and 5-year of HCC patients.Conclusion: Our results provided novel evidences that NRs could act as the potential prognostic signatures for HCC patients.

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“…Thus, the mechanism of EMT-associated chemotherapy resistance is complicated and unknown, and more works are needed to gure out the mechanism of EMT-associated chemotherapy resistance. LIM-only protein FHLs, including FHL1, FHL2, and FHL3, are characterized by evolutionarily conserved LIM domains and one conserved LIM superfamily domain [26]. FHLs are reported as the transcriptional factors, which participate in lots of signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

“…FHLs are reported as the transcriptional factors, which participate in lots of signaling pathways. Simply, FHL1-2 are reported in regulation of TGFβ/Smad-independent pathway, such as PI3K/Akt, Wnt/β-catenin, and MAPK/ERK pathways, through which FHLs participate in EMT process and chemo-radio-therapy resistance in pancreatic cancer, breast cancer, and osteosarcoma [27,7,26]. Besides, FHL1-3 are considered as inhibitors of cell cycle checkpoints CDC25, through which they lead to radioresistance in pancreatic cancer and HeLa cell line [28].…”

Section: Introductionmentioning

confidence: 99%

FHL3 Contributes to EMT and Chemotherapy Resistance Through Inhibiting Ubiquitination of Slug and Activating TGFβ/Smad-Independent Pathways in Gastric Cancer

Cao

Sun

Chen

et al. 2020

Preprint

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Background: Gastric cancer presents high risk of metastasis and chemotherapy resistance. Hence, the mechanistic understanding of the tumor metastasis and chemotherapy resistance is quietly important.Methods: TCGA database and clinical samples are used for exploring the role of FHL3 in disease progression and prognosis. The roles of FHL3 in metastasis and chemotherapy resistance are explored in vitro and in vivo by siRNA or shRNA treatment. Finally, we explore the FHL3-mediated EMT and chemotherapy resistance.Results: mRNA and protein level of FHL3 is significantly up-regulated in gastric cancer tissues when compares with it in adjacent tissue. Higher expression level of FHL3 companies with worse overall survival in gastric cancer. OPH resistance cells show higher level of FHL3 and mesenchymal phenotype. Knockdown of FHL3 slightly inhibits the cell growth, while it obviously sensitizes the chemotherapy in vivo and in vitro. In addition, down-regulation of FHL3 decreases the mesenchymal markers, such as Slug, Snail, Twist1, and vimentin, while increases the epithelial marker E-cadherin. For mechanism study, FHL3 knockdown down-regulates the expression level or activity of MAPK/ERK pathway and TGFβ/PI3K/Akt/GSK3β-RNF146/ubiquitin pathway in OPH resistance cells. Mesenchymal phenotype cells hold higher level of MDR1, and the FHL3 knockdown reverts the MDR1 in this type cell. Conclusion: FHL3 is a risk of disease progression in gastric cancer. MAPK and PI3K pathways were activated when FHL3 induces EMT and drug resistance process, but the TGFβ/Smad -dependent pathway did not participate in the process. FHL3 competitively bond the ubiquitin complex (slug/GSK3β/RNF146) with slug, inhibit ubiquitination of Slug.

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An emerging link between LIM domain proteins and nuclear receptors

Cited by 29 publications

References 95 publications

LIMK2 promotes the metastatic progression of triple-negative breast cancer by activating SRPK1

LIMK2 promotes the metastatic progression of triple-negative breast cancer by activating SRPK1

Human Nuclear Receptors (NRs) Genes Have Prognostic Significance in Hepatocellular Carcinoma Patients

FHL3 Contributes to EMT and Chemotherapy Resistance Through Inhibiting Ubiquitination of Slug and Activating TGFβ/Smad-Independent Pathways in Gastric Cancer

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