scholarly journals Tyrosyl Phosphorylated PAK1 Regulates Breast Cancer Cell Motility in Response to Prolactin through Filamin A

2013 ◽  
Vol 27 (3) ◽  
pp. 455-465 ◽  
Author(s):  
Alan Hammer ◽  
Leah Rider ◽  
Peter Oladimeji ◽  
Leslie Cook ◽  
Quanwen Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cell Motility ◽  
Small Gtpase ◽  
Actin Binding ◽  
Filamin A ◽  
T47d Cells ◽  
Tyrosine Kinase 2 ◽  
Janus Tyrosine Kinase 2

Abstract The p21-activated serine-threonine kinase (PAK1) is activated by small GTPase-dependent and -independent mechanisms and regulates cell motility. Both PAK1 and the hormone prolactin (PRL) have been implicated in breast cancer by numerous studies. We have previously shown that the PRL-activated tyrosine kinase JAK2 (Janus tyrosine kinase 2) phosphorylates PAK1 in vivo and identified tyrosines (Tyr) 153, 201, and 285 in the PAK1 molecule as sites of JAK2 tyrosyl phosphorylation. Here, we have used human breast cancer T47D cells stably overexpressing PAK1 wild type or PAK1 Y3F mutant in which Tyr(s) 153, 201, and 285 were mutated to phenylalanines to demonstrate that phosphorylation of these three tyrosines are required for maximal PRL-dependent ruffling. In addition, phosphorylation of these three tyrosines is required for increased migration of T47D cells in response to PRL as assessed by two independent motility assays. Finally, we show that PAK1 phosphorylates serine (Ser) 2152 of the actin-binding protein filamin A to a greater extent when PAK1 is tyrosyl phosphorylated by JAK2. Down-regulation of PAK1 or filamin A abolishes the effect of PRL on cell migration. Thus, our data presented here bring some insight into the mechanism of PRL-stimulated motility of breast cancer cells.

Periplaneta Americana Extract May Attenuate Renal Fibrosis through Inhibiting Janus Tyrosine Kinase 2/Signal Transducer and Activator of Transcription 3 Pathway

Pharmacology ◽  
2018 ◽  
Vol 102 (1-2) ◽  
pp. 1-8 ◽  
Author(s):  
Jingsong Liu ◽  
Lin Zhou ◽  
Liyu He ◽  
Ying Zhong ◽  
Xiaobai Zhang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Renal Fibrosis ◽  
Periplaneta Americana ◽  
Smooth Muscle Actin ◽  
Signal Transducer ◽  
Alpha Smooth Muscle Actin ◽  
Tyrosine Kinase 2 ◽  
Janus Tyrosine Kinase 2 ◽  
Transcription 3

Background: Periplaneta americana is one of the ancient insect groups with the strongest vitality. Periplaneta americana extract (PAE) has been explored as an alternative remedy for many diseases. Although much progress has been made in the study about PAE, the role of the drug in renal disease is rarely reported, especially in renal fibrosis. This study was designed to evaluate the renoprotective effect of PAE treatment to renal fibrosis. Method: An in vivo, unilateral ureteral obstruction (UUO) mouse model was built. Then the mice were treated with PAE (100 mg/kg body weight) once daily by oral gavage, again starting on the day of UUO and continued for 1 week. At the end of 1 week, the mice were sacrificed; kidney samples were collected for further analysis. In vitro, Boston University mouse proximal tubular cells were plated in 35-mm dishes at a density of 0.3 * 106 cells/dish. Then the cells were treated with 5-ng/mL TGF-β1 in serum-free DMEM medium for an indicated length of time. The experimental groups were pretreated with the indicated concentrations of PAE (0.3125 mg/mL). The cells were further cultured for 24 h, and then cells were monitored morphologically or collected for biochemical analyses. Results: Both in vivo and vitro PAE inhibits the expression of FN and alpha-smooth muscle actin and suppresses renal fibrosis. Importantly, PAE protects against renal fibrosis by inhibiting Janus tyrosine kinase 2 (JAK)/signal transducer and activator of transcription 3 (STAT) tyrosine phosphorylation. Conclusion: PAE attenuates renal fibrosis through the suppression of the JAK2/STAT3 pathway.

scholarly journals A Folate- and Vitamin B12-Deficient Diet Decreases the Latency and Increases the Incidence of Mammary Tumors in MMTV-ErbB2 Transgenic Mice

2021 ◽  
Author(s):  
Zhengzheng Xiao ◽  
Guoliang Yao ◽  
Yongxuan Liu ◽  
Chunling Zhao
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Vitamin B12 ◽  
Signaling Pathways ◽  
Mammary Tumor ◽  
Receptor Tyrosine Kinase ◽  
Tumor Development ◽  
Deficient Diet ◽  
Tyrosine Kinase 2 ◽  
Folate And Vitamin B12

Abstract There has been controversy regarding folate- and vitamin B12-deficient diet (FVD)-induced hyperhomocysteinemia (HHcy) associated with breast cancer risk in most published epidemiological studies. Thus, the present study designed experiments to assess the causal association between FVD-induced HHcy and mammary tumor risk, as well as to identify the relative underlying mechanism. In this study, mammary tumor development was examined in mouse mammary tumor virus (MMTV)-erb-b2 receptor tyrosine kinase 2 (ErbB2) mice fed with a control AIN-93G diet or a FVD diet. MMTV-ErbB2 mice fed with the FVD diet displayed elevated blood levels of the amino acid homocysteine, a shorter tumor latency and an increased tumor multiplicity compared with the controls. The expression levels of key markers in the receptor tyrosine kinase and estrogen receptor (ER) signaling pathways, including phosphorylated (p)-Akt, p-Erk, p-ERα and Cyclin D1, were elevated in mammary tissues from MMTV-ErbB2 mice fed the FVD diet compared with mice fed with control diet. These data suggested that FVD-induced HHcy may promote mammary tumor development and decrease tumor latency, possibly by activating the epidermal growth factor receptor/ErbB2 and ERα signaling pathways. Therefore, examining the signaling mechanisms and identifying the relative metabolic pathways underlying mammary tumor promotion following FVD-induced HHcy may provide a novel strategy for breast cancer prevention and treatment.

scholarly journals Regulation of the formation of osteoclastic actin rings by proline-rich tyrosine kinase 2 interacting with gelsolin

2003 ◽  
Vol 160 (4) ◽  
pp. 565-575 ◽  
Author(s):  
Qiang Wang ◽  
Yi Xie ◽  
Quan-Sheng Du ◽  
Xiao-Jun Wu ◽  
Xu Feng ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Tyrosine Kinase ◽  
Actin Polymerization ◽  
Actin Binding ◽  
Cell Periphery ◽  
Cytoskeletal Organization ◽  
Capping Protein ◽  
Tyrosine Kinase 2 ◽  
Multiple Cells ◽  
Actin Rings

Osteoclast activation is important for bone remodeling and is altered in multiple bone disorders. This process requires cell adhesion and extensive actin cytoskeletal reorganization. Proline-rich tyrosine kinase 2 (PYK2), a major cell adhesion–activated tyrosine kinase in osteoclasts, plays an important role in regulating this event. The mechanisms by which PYK2 regulates actin cytoskeletal organization and osteoclastic activation remain largely unknown. In this paper, we provide evidence that PYK2 directly interacts with gelsolin, an actin binding, severing, and capping protein essential for osteoclastic actin cytoskeletal organization. The interaction is mediated via the focal adhesion–targeting domain of PYK2 and an LD motif in gelsolin's COOH terminus. PYK2 phosphorylates gelsolin at tyrosine residues and regulates gelsolin bioactivity, including decreasing gelsolin binding to actin monomer and increasing gelsolin binding to phosphatidylinositol lipids. In addition, PYK2 increases actin polymerization at the fibroblastic cell periphery. Finally, PYK2 interacts with gelsolin in osteoclasts, where PYK2 activation is required for the formation of actin rings. Together, our results suggest that PYK2 is a regulator of gelsolin, revealing a novel PYK2–gelsolin pathway in regulating actin cytoskeletal organization in multiple cells, including osteoclasts.

scholarly journals 17β-Estradiol Enhances Breast Cancer Cell Motility and Invasion via Extra-Nuclear Activation of Actin-Binding Protein Ezrin

PLoS ONE ◽  
2011 ◽  
Vol 6 (7) ◽  
pp. e22439 ◽  
Author(s):  
Shuhui Zheng ◽  
Jinghe Huang ◽  
Kewen Zhou ◽  
Chengxi Zhang ◽  
Qiuling Xiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Motility ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Binding Protein ◽  
Actin Binding ◽  
Actin Binding Protein ◽  
Cancer Cell Motility ◽  
Nuclear Activation ◽  
17Β Estradiol

scholarly journals MDM2 Promotes Cell Motility and Invasiveness by Regulating E-Cadherin Degradation

2006 ◽  
Vol 26 (19) ◽  
pp. 7269-7282 ◽  
Author(s):  
Jer-Yen Yang ◽  
Cong S. Zong ◽  
Weiya Xia ◽  
Yongkun Wei ◽  
Mohamed Ali-Seyed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Motility ◽  
Cancer Metastasis ◽  
Ectopic Expression ◽  
Dominant Negative ◽  
Antibody Array ◽  
Breast Cancer Patients ◽  
Mdm2 Gene ◽  
E Cadherin

ABSTRACT Gene amplification and protein overexpression of MDM2, which is often found in certain types of cancers, indicate that MDM2 plays an important role in tumorigenesis. Interestingly, several clinical reports have demonstrated that amplification of the MDM2 gene correlates with the metastatic stage. Using an antibody array assay, we identified E-cadherin as an MDM2-binding protein and confirmed that E-cadherin is a substrate for the MDM2 E3 ubiquitin ligase. We demonstrate that MDM2 interacts in vivo with E-cadherin, resulting in its ubiquitination and degradation. This regulation appears to be clinically relevant, as we found a significant correlation between high MDM2 and low E-cadherin protein levels in resected tumor specimens recovered from breast cancer patients with lymph node metastases. Ectopic expression of MDM2 in breast cancer cells was found to disrupt cell-cell contacts and enhance cell motility and invasive potential. We found that E-cadherin and MDM2 colocalized on the plasma membrane and in the early endosome, where ubiquitin moieties were attached to E-cadherin. Blocking endocytosis with dominant-negative mutants of dynamin abolished the association of MDM2 with E-cadherin, prevented E-cadherin degradation, and attenuated cell motility as observed by fluorescence microscopy. Thus, we provide evidence to support a novel role for MDM2 in regulating cell adhesions by a mechanism that involves degrading and down-regulating the expression of E-cadherin via an endosome pathway. This novel MDM2-regulated pathway is likely to play a biologically relevant role in cancer metastasis.

scholarly journals Receptor Tyrosine Kinase Ror2 Mediates Wnt5a-induced Polarized Cell Migration by Activating c-Jun N-terminal Kinase via Actin-binding Protein Filamin A

2008 ◽  
Vol 283 (41) ◽  
pp. 27973-27981 ◽  
Author(s):  
Akira Nomachi ◽  
Michiru Nishita ◽  
Daisuke Inaba ◽  
Masahiro Enomoto ◽  
Mayumi Hamasaki ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Binding Protein ◽  
Actin Binding ◽  
Filamin A ◽  
Actin Binding Protein

scholarly journals The Wnt-5a–Derived Hexapeptide Foxy-5 Inhibits Breast Cancer Metastasis In vivo by Targeting Cell Motility

2008 ◽  
Vol 14 (20) ◽  
pp. 6556-6563 ◽  
Author(s):  
Annette Säfholm ◽  
Johanna Tuomela ◽  
Jeanette Rosenkvist ◽  
Janna Dejmek ◽  
Pirkko Härkönen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Motility ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis

scholarly journals Interaction of activated Cdc42-associated tyrosine kinase ACK2 with HSP90

2004 ◽  
Vol 382 (1) ◽  
pp. 199-204 ◽  
Author(s):  
Wannian YANG ◽  
Jaclyn M. JANSEN ◽  
Qiong LIN ◽  
Sabrina CANOVA ◽  
Richard A. CERIONE ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Heat Shock Protein 90 ◽  
Kinase Domain ◽  
Atpase Inhibitor ◽  
Sorting Nexin ◽  
Downstream Effector ◽  
Tyrosine Kinase 2 ◽  
Functional Complex

ACK2 (activated Cdc42-associated tyrosine kinase 2) is a specific downstream effector for Cdc42, a member of the Rho family of small G-proteins. ACK2 interacts with clathrin, an endocytic vesicle coating protein, and SH3PX1, a sorting nexin, and is involved in clathrin-mediated endocytosis. While searching for proteins that interact with ACK2, we found that HSP90 (heat-shock protein 90) binds to ACK2. Analysis of a series of truncation mutants of ACK2 has defined the regions within the kinase domain of ACK2 that are required for binding to HSP90. The binding of HSP90 to ACK2 is blocked upon treatment with geldanamycin, an HSP90-specific ATPase inhibitor, and is required for the in vivo kinase activity of ACK2 and its association with Cdc42. Overall, our data suggest a novel mechanism of regulation in which HSP90 serves as a regulatory component in an ACK2 functional complex and plays a role in sustaining its kinase activity.

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