scholarly journals Novel Association of Vav2 and Nek3 Modulates Signaling through the Human Prolactin Receptor

2005 ◽  
Vol 19 (4) ◽  
pp. 939-949 ◽  
Author(s):  
Sommer L. Miller ◽  
Jamie E. DeMaria ◽  
David O. Freier ◽  
Angela M. Riegel ◽  
Charles V. Clevenger
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Prolactin Receptor ◽  
Chinese Hamster ◽  
Receptor Activation ◽  
Signal Transducer ◽  
Nucleotide Exchange ◽  
T47d Cells ◽  
Related Family ◽  
Guanosine Triphosphatase

Abstract Prolactin (PRL) receptor activation contributes to the progression and motility of human breast cancer. This event activates multimeric signaling pathways, including the activation of the Vav family of guanine nucleotide exchange factors. To detect novel proteins interacting with Vav, yeast two-hybrid analysis was performed and demonstrated an interaction between the serine/threonine NIMA (never in mitosis A)-related family kinase p56Nek3 and Vav1. The PRL-dependent interaction of Nek3 with Vav1 and Vav2 was confirmed by coimmunoprecipitation analysis. PRL stimulation of T47D cells induced Nek3 kinase activity and the interaction of Vav2/Nek3 with the PRL receptor. Increased Nek3 levels up-regulated Vav2 serine and tyrosine phosphorylation, whereas knockdown of Nek3 resulted in a reduction of Vav2 phosphorylation. Activation of guanosine triphosphatase Rac-1 in Chinese hamster ovary transfectants required both Nek3 and Vav2 and was inhibited by the overexpression of a kinase inactivating Nek3 mutant. However, overexpression of either Nek3 or kinase-inactive Nek3 had no effect on Vav2-potentiated signal transducer and activator of transcription 5-mediated gene expression. Overexpression of kinase inactive Nek3 in T47D cells led to a 50% increase in apoptosis vs. controls. These data suggest that the PRL-mediated activation of Nek3 contributes differentially to Vav2 signaling pathways involving Rac1 and signal transducer and activator of transcription 5 and implicates Nek3 during PRL-mediated actions in breast cancer.

CAML promotes prolactin-dependent proliferation of breast cancer cells by facilitating prolactin receptor signaling pathways

2010 ◽  
Vol 130 (1) ◽  
pp. 19-27 ◽  
Author(s):  
Ji-Hong Lim ◽  
Tae-You Kim ◽  
Woo-Ho Kim ◽  
Jong-Wan Park
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Breast Cancer Cells ◽  
Prolactin Receptor ◽  
Receptor Signaling

scholarly journals Activation of the RalGEF/Ral Pathway Promotes Prostate Cancer Metastasis to Bone

2007 ◽  
Vol 27 (21) ◽  
pp. 7538-7550 ◽  
Author(s):  
JuanJuan Yin ◽  
Claire Pollock ◽  
Kirsten Tracy ◽  
Monika Chock ◽  
Philip Martin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathways ◽  
Cell Line ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Receptor Activation ◽  
Organ Specificity ◽  
Tyrosine Kinase Receptor ◽  
Nucleotide Exchange ◽  
Prostate Cancer Metastasis

ABSTRACT A hallmark of metastasis is organ specificity; however, little is known about the underlying signaling pathways responsible for the colonization and growth of tumor cells in target organs. Since tyrosine kinase receptor activation is frequently associated with prostate cancer progression, we have investigated the role of a common signaling intermediary, activated Ras, in prostate cancer metastasis. Three effector pathways downstream of Ras, Raf/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase, and Ral guanine nucleotide exchange factors (RalGEFs), were assayed for their ability to promote the metastasis of a tumorigenic, nonmetastatic human prostate cancer cell line, DU145. Oncogenic Ras promoted the metastasis of DU145 to multiple organs, including bone and brain. Activation of the Raf/ERK pathway stimulated metastatic colonization of the brain, while activation of the RalGEF pathway led to bone metastases, the most common organ site for prostate cancer metastasis. In addition, loss of RalA in the metastatic PC3 cell line inhibited bone metastasis but did not affect subcutaneous tumor growth. Loss of Ral appeared to suppress expansive growth of prostate cancer cells in bone, whereas homing and initial colonization were less affected. These data extend our understanding of the functional roles of the Ral pathway and begin to identify signaling pathways relevant for organ-specific metastasis.

scholarly journals Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 146 ◽  
Author(s):  
Yu Zhang ◽  
Jun Li ◽  
Xing-Ning Lai ◽  
Xue-Qiao Jiao ◽  
Jun-Ping Xiong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Malignant Tumors ◽  
Target Therapy ◽  
Nucleotide Exchange ◽  
Surface Receptors ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Non Coding Rnas ◽  
Guanosine Triphosphatase

Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide-exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer.

scholarly journals BNIP-2 retards breast cancer cell migration by coupling microtubule-mediated GEF-H1 and RhoA activation

2020 ◽  
Vol 6 (31) ◽  
pp. eaaz1534 ◽  
Author(s):  
Meng Pan ◽  
Ti Weng Chew ◽  
Darren Chen Pei Wong ◽  
Jingwei Xiao ◽  
Hui Ting Ong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Focal Adhesions ◽  
Fine Tuning ◽  
Nucleotide Exchange ◽  
Microtubule Depolymerization ◽  
Cell Contractility ◽  
Rhoa Activity ◽  
Rhoa Activation ◽  
Guanosine Triphosphatase

Microtubules display dynamic turnover during cell migration, leading to cell contractility and focal adhesion maturation regulated by Rho guanosine triphosphatase activity. This interplay between microtubules and actomyosin is mediated by guanine nucleotide exchange factor (GEF)–H1 released after microtubule depolymerization or microtubule disconnection from focal adhesions. However, how GEF-H1 activates Rho upon microtubule disassembly remains elusive. Here, we found that BNIP-2, a BCH domain–containing protein that binds both RhoA and GEF-H1 and traffics with kinesin-1 on microtubules, is important for GEF-H1–driven RhoA activation upon microtubule disassembly. Depletion of BNIP-2 in MDA-MB-231 breast cancer cells decreases RhoA activity and promotes cell migration. Upon nocodazole-induced microtubule disassembly, the interaction between BNIP-2 and GEF-H1 increases, while knockdown of BNIP-2 reduces RhoA activation and cell rounding via uncoupling RhoA-GEF-H1 interaction. Together, these findings revealed that BNIP-2 couples microtubules and focal adhesions via scaffolding GEF-H1 and RhoA, fine-tuning RhoA activity and cell migration.

scholarly journals Role of c-Myb during Prolactin-Induced Signal Transducer and Activator of Transcription 5a Signaling in Breast Cancer Cells

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1597-1606 ◽  
Author(s):  
Feng Fang ◽  
Michael A. Rycyzyn ◽  
Charles V. Clevenger
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Prolactin Receptor ◽  
Ectopic Expression ◽  
Cellular Level ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Signaling Complex

Implicated in the pathogenesis of breast cancer, prolactin (PRL) mediates its function in part through the prolactin receptor (PRLr)-associated Janus kinase 2 (Jak2)/signal transducer and activator of transcription 5 (Stat5) signaling complex. To delineate the mechanisms of Stat5a regulation in breast cancer, transcription factor-transcription factor (TF-TF) array analysis was employed to identify associated transcriptional regulators. These analyses revealed a PRL-inducible association of Stat5a with the transcription factor and protooncogene c-Myb. Confirmatory co-immunoprecipitation studies using lysates from both T47D and MCF7 breast cancer cells revealed a PRL-inducible association between these transcription factors. Ectopic expression of c-Myb enhanced the PRL-induced expression from both composite and synthetic Stat5a-responsive luciferase reporters. Chromatin immunoprecipitation assays also revealed a PRL-inducible association between c-Myb and endogenous Stat5a-responsive CISH promoter, which was associated with an enhanced expression of CISH gene product at the RNA and protein levels. Small interfering RNA-mediated c-Myb knockdown impaired the PRL-induced mRNA expression of five Stat5-responsive genes. DNA binding-defective mutants of c-Myb, incapable of activating expression from a c-Myb-responsive reporter, maintained their ability to enhance a Stat5a-responsive reporter. At a cellular level, ectopic expression of c-Myb resulted in an increase in T47D proliferation. Taken together, these results indicate that c-Myb potentiates Stat5a-driven gene expression, possibly functioning as a Stat5a coactivator, in human breast cancer.

scholarly journals Progestins Induce Transcriptional Activation of Signal Transducer and Activator of Transcription 3 (Stat3) via a Jak- and Src-Dependent Mechanism in Breast Cancer Cells

2005 ◽  
Vol 25 (12) ◽  
pp. 4826-4840 ◽  
Author(s):  
Cecilia Proietti ◽  
Mariana Salatino ◽  
Cinthia Rosemblit ◽  
Romina Carnevale ◽  
Adalí Pecci ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Phosphorylation ◽  
Transcriptional Activation ◽  
Expression Vector ◽  
Dominant Negative ◽  
Steroid Hormone Receptors ◽  
Signal Transducer ◽  
T47d Cells ◽  
Stat3 Phosphorylation

ABSTRACT Interactions between steroid hormone receptors and signal transducer and activator of transcription (Stat)-mediated signaling pathways have already been described. In the present study, we explored the capacity of progestins to modulate Stat3 transcriptional activation in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in BALB/c mice and in the human breast cancer cell line T47D. We found that C4HD epithelial cells, from the MPA-induced mammary tumor model, expressed Stat3 and that MPA treatment of C4HD cells up-regulated Stat3 protein expression. In addition, MPA induced rapid, nongenomic Stat3, Jak1, and Jak2 tyrosine phosphorylation in C4HD and T47D cells. MPA treatment of C4HD cells also resulted in rapid c-Src tyrosine phosphorylation. These effects were completely abolished by the progestin antagonist RU486. Abrogation of Jak1 and Jak2 activity by transient transfection of C4HD cells with dominant negative (DN) Jak1 or DN Jak2 vectors, or inhibition of Src activity by preincubation of cells with the Src family kinase inhibitor PP2, blocked the capacity of MPA to induce Stat3 phosphorylation. Treatment of C4HD cells with MPA induced Stat3 binding to DNA. In addition, MPA promoted strong Stat3 transcriptional activation in C4HD and T47D cells that was inhibited by RU486 and by blockage of Jak1, Jak2, and Src activities. To investigate the correlation between MPA-induced Stat3 activation and cell growth, C4HD cells were transiently transfected with a DN Stat3 expression vector, Stat3Y705-F, or with a constitutively activated Stat3 mutant, Stat3-C. While expression of Stat3Y705-F mutant had an inhibitory effect on MPA-induced growth of C4HD cells, transfection with the constitutively activated Stat3-C vector resulted in MPA-independent proliferation. Finally, we addressed the effect of targeting Stat3 in in vivo growth of C4HD breast tumors. Blockage of Stat3 activation by transfection of C4HD cells with the DN Stat3Y705-F expression vector significantly inhibited these cells' ability to form tumors in syngeneic mice. Our results have for the first time demonstrated that progestins are able to induce Stat3 transcriptional activation, which is in turn an obligatory requirement for progestin stimulation of both in vitro and in vivo breast cancer growth.

Apoptosis induction and cell cycle alterations by extract of Pistacia atlantica (Baneh) in comparison to tamoxifen in human breast cancer T47D cells

Planta Medica ◽  
2007 ◽  
Vol 73 (09) ◽  
Author(s):  
YY Kamrani ◽  
S Fouladdel ◽  
T Asgari ◽  
G Amin ◽  
B Esmaeelian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Human Breast Cancer ◽  
Apoptosis Induction ◽  
Human Breast ◽  
T47d Cells ◽  
Pistacia Atlantica ◽  
Cell Cycle Alterations
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