CrkL is a Co-Activator of Estrogen Receptor α That Enhances Tumorigenic Potential in Cancer

Padmanabhan, Renjini Ambika; Nirmala, Lini; Murali, Megha; Laloraya, Malini

doi:10.1210/me.2011-0008

Cited by 13 publications

(11 citation statements)

References 43 publications

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“…CAV1, PLEC for higher ratios of EGFR vs. ERBB2 and GRB7, CRKL and CTNND1 for higher ratios of ERBB2 vs. EGFR. CRKL has been shown to associate with lamellipodia formation in breast carcinoma 37 , and coactivation of CRKL and estrogen receptor alpha has been shown to be a promoter of tumorigenesis 38 . These observations are supported by literature reports, such as CTNND1 was genomically correlated to breast cancer and cell proliferation in ERBB2 positive breast cancer cell lines 39–41 .…”

Section: Resultsmentioning

confidence: 99%

Genome Wide Proteomics of ERBB2 and EGFR and Other Oncogenic Pathways in Inflammatory Breast Cancer

et al. 2013

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In this study we selected three breast cancer cell lines (SKBR3, SUM149 and SUM190) with different oncogene expression levels involved in ERBB2 and EGFR signaling pathways as a model system for the evaluation of selective integration of subsets of transcriptomic and proteomic data. We assessed the oncogene status with RPKM values (Reads Per Kilobase per Million mapped reads1) for ERBB2 (14.4, 400 and 300 for SUM149, SUM 190 and SKBR3 respectively and for EGFR 60.1, not detected and 1.4 for the same 3 cell lines. We then used RNA-Seq data to identify those oncogenes with significant transcript levels in these cell lines (total 31) and interrogated the corresponding proteomics data sets for proteins with significant interaction values with these oncogenes. The number of observed interactors for each oncogene showed a significant range, e.g. 4.2% (JAK1) to 27.3% (MYC). The percentage is measured as a fraction of the total protein interactions in a given data set vs. total interactors for that oncogene in STRING (Search Tool for the Retrieval of Interacting Genes/Proteins, version 9.0) and I2D (Interologous Interaction Database, version 1.95). This approach allowed us to focus on 4 main oncogenes, ERBB2, EGFR, MYC, and GRB2, for pathway analysis. We used the following bioinformatics sites, GeneGo, PathwayCommons and NCI receptor signaling networks to identify pathways which contained the four main oncogenes, had good coverage in the transcriptomic and proteomic data sets as well as significant number of oncogene interactors. The four pathways identified were ERBB signaling, EGFR1 signaling, integrin outside-in signaling, and validated targets of C-MYC transcriptional activation. The greater dynamic range of the RNA-Seq values allowed the use of transcript ratios to correlate observed protein values with the relative levels of the ERBB2 and EGFR transcripts in each of the four pathways. This provided us with potential proteomic signatures for the SUM149 and 190 cell lines, growth factor receptor-bound protein 7 (GRB7), Crk-like protein (CRKL) and Catenin delta-1 (CTNND1) for ERBB signaling, caveolin 1 (CAV1), plectin (PLEC) for EGFR signaling; filamin A (FLNA) and actinin alpha1 (ACTN1) (associated with high levels of EGFR transcript) for integrin signalings: branched chain amino-acid transaminase 1 (BCAT1), carbamoyl-phosphate synthetase (CAD), nucleolin (NCL) (high levels of EGFR transcript); transferrin receptor (TFRC), metadherin (MTDH) (high levels of ERBB2 transcript) for MYC signaling; S100-A2 protein (S100A2), caveolin 1 (CAV1), Serpin B5 (SERPINB5), stratifin (SFN), PYD and CARD domain containing (PYCARD), and EPH receptor A2 (EPHA2) for PI3K signaling, p53 sub-pathway. Future studies of inflammatory breast cancer (IBC), from which the cell lines were derived, will be used to explore the significance of these observations.

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Section: Resultsmentioning

confidence: 99%

Genome Wide Proteomics of ERBB2 and EGFR and Other Oncogenic Pathways in Inflammatory Breast Cancer

et al. 2013

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“…For the identification of the interacting partners, immunoprecipitation studies followed by MALDI TOF analysis were performed as described previously (Padmanabhan et al, 2011). Briefly, 200 mg of nuclear or cytosolic extracts were incubated with 1 mg of primary antibody.…”

Section: Immunoprecipitation and Maldi Tof Analysis To Identify Intermentioning

confidence: 99%

STAT3 and MCL-1 associate to cause a mesenchymal epithelial transition

Renjini

Titus

Narayan

et al. 2014

Journal of Cell Science

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Embryo implantation is effected by a myriad of signaling cascades acting on the embryo-endometrium axis. Here we show, by using MALDI TOF analysis, far-western analysis and colocalization and co-transfection studies, that STAT3 and MCL-1 are interacting partners during embryo implantation. We show in vitro that the interaction between the two endogenous proteins is strongly regulated by estrogen and progesterone. Implantation, pregnancy and embryogenesis are distinct from any other process in the body, with extensive, but controlled, proliferation, cell migration, apoptosis, cell invasion and differentiation. Cellular plasticity is vital during the early stages of development for morphogenesis and organ homeostasis, effecting the epithelial to mesenchymal transition (EMT) and, the reverse process, mesenchymal to epithelial transition (MET). STAT3 functionally associates with MCL-1 in the mammalian breast cancer cell line MCF7 that overexpresses STAT3 and MCL-1, which leads to an increased rate of apoptosis and decreased cellular invasion, disrupting the EMT. Association of MCL-1 with STAT3 modulates the normal, antiapoptotic, activity of MCL-1, resulting in pro-apoptotic effects. Studying the impact of the association of STAT3 with MCL-1 on MET could lead to an enhanced understanding of pregnancy and infertility, and also metastatic tumors.

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“…CRKL protein level was upregulated in BC tissues compared with adjacent normal tissues [57]. Its overexpression correlated well with advanced TNM stage, lymph node metastasis and tumor size, while, showed no clear association with estrogen receptor (ER), progesterone receptor and ErbB-2 status.…”

Section: Crkl and Breast Cancermentioning

confidence: 98%

The Role of CT10 Regulation of Kinase-Like in Cancer

2014

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V-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) is a member of CRK family. It acts as an adaptor protein in intracellular signal transduction. CRKL has been reported overexpressed in a variety of cancers affecting the aggressive and malignant behaviors of cancer cells. CRKL seems to show a tumor-promotion role in gastric cancer, glioblastoma multiforme, hepatocellular carcinoma, bladder cancer, lung cancer, colon cancer, ovarian cancer, leukemia, breast cancer, head and neck cancer, rhabdomyosarcoma and neuroblastoma. The association of CRKL with malignant tumors and its potential action mechanisms were summarized. CRKL has the potential to be used as a biomarker for the diagnosis, treatment and prognosis of certain tumors.

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CrkL is a Co-Activator of Estrogen Receptor α That Enhances Tumorigenic Potential in Cancer

Cited by 13 publications

References 43 publications

Genome Wide Proteomics of ERBB2 and EGFR and Other Oncogenic Pathways in Inflammatory Breast Cancer

Genome Wide Proteomics of ERBB2 and EGFR and Other Oncogenic Pathways in Inflammatory Breast Cancer

STAT3 and MCL-1 associate to cause a mesenchymal epithelial transition

The Role of CT10 Regulation of Kinase-Like in Cancer

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