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

Hammer, Alan; Rider, Leah; Oladimeji, Peter; Cook, Leslie; Li, Quanwen; Mattingly, Raymond R.; Diakonova, Maria

doi:10.1210/me.2012-1291

Cited by 32 publications

(50 citation statements)

References 80 publications

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“…Several investigations have suggested that Tyr-phosphorylated PAK1 could be crucially involved in the regulation of cancer cell migration (14,28,47). On the basis of the mechanisms underlying EMT regulation, we focused on a nuclear factor as a downstream target of PAK1 that could confer radioresistant properties on NSCLC cells.…”

Section: Discussionmentioning

confidence: 99%

PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells

et al. 2014

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The p21-activated Ser/Thr kinase 1 (PAK1) kinase has an essential role in tumorigenesis and cell survival in many cancers, but its regulation is not fully understood. In this study, we showed that in response to irradiation of lung cancer cells, PAK1 was upregulated, tyrosine phosphorylated, and translocated to the nucleus. Tyrosine phosphorylation relied upon JAK2 kinase activity and was essential for PAK1 protein stability and binding to Snail. This radiation-induced JAK2-PAK1-Snail signaling pathway increased epithelial-mesenchymal transition (EMT) by regulating epithelial and mesenchymal cell markers. Notably, JAK2 inhibitors mediated radiosensitization and EMT blockade in a mouse xenograft model of lung cancer. Taken together, our findings offered evidence that JAK2 phosphorylates and stabilizes functions of PAK1 that promote EMT and radioresistance in lung cancer cells, with additional implications for the use of JAK2 inhibitors as radiosensitizers in lung cancer treatment.

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Section: Discussionmentioning

confidence: 99%

PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells

et al. 2014

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“…On the other hand, FlnA deficiency in breast cancer cells significantly reduces their migration and invasion by interacting with Cyclin D1 [49,50]. Up-regulation of phosphorylated PAK1 can increase breast cancer cell motility through FlnA [51].…”

Section: Breast Cancermentioning

confidence: 99%

Filamin A: Insights into its Exact Role in Cancers

Shao

Zhang

Zhao

et al. 2015

Pathol. Oncol. Res.

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Filamin A (FlnA) is a well-known actin cross-linking protein. It serves as a scaffold for over 90 binding partners and involves in multiple cell functions, of which cell migration and adhesion is especially critical. Recently, its role in the cell has come under scrutiny for FlnA's involvement in cancer development. Originally revealed as a cancer-promoting protein, FlnA actually plays a dual role in cancers. When localized to the cytoplasm, FlnA has a tumor-promoting effect by interacting with signaling molecules. While once localized to the nucleus, it may act to suppress tumor growth and inhibit metastasis by interacting with transcription factors. Thus drugs that can cause FlnA to transpose from cytoplasm to nucleus could be a promising treatment for cancers. Study to this end is on the way in prostate cancer and the results are encouraging. FlnA has been studied in large categories of cancers, such as prostate cancer, breast cancer, melanoma, lung cancer, etc. However, most studies did not evaluate the differences that arise from the localization of the protein, which was a great pity! What's more, although FlnA's is undoubtedly important in cancer invasion and metastasis, both preclinical and clinical researches are very rare in some highly metastatic cancers, such as pancreatic cancer. In this mini-review, we give a comprehensive summary of FlnA' s expression in cancers. Where available, we also indicate the correlation of FlnA with cancer stages and patient prognosis, and clarify its localization (nucleus/cytoplasm) and its dual role (promote/suppress) in different cancers.

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“…PAK1 is known to be activated by both PRL [14,15] and E2 ([8,20]. However, nuclear PAK1 kinase activity has not been demonstrated previously.…”

Section: Resultsmentioning

confidence: 99%

“…Tyrosyl phosphorylation of PAK1 (pTyr-PAK1) enhances such important PAK1 functions as kinase activity and the ability to form protein/protein interactions that are important for adhesion, motility, and invasion of breast cancer cells in response to PRL ([14,15,16]; reviewed in [17]). We have also previously demonstrated that the three tyrosines on PAK1 molecules and PAK1-Nck interaction play a critical role in PAK1-dependent regulation of cyclin D1 promoter activity in response to PRL [18].…”

Section: Introductionmentioning

confidence: 99%

PAK1 translocates into nucleus in response to prolactin but not to estrogen

Oladimeji

Diakonova

2016

Biochemical and Biophysical Research Communications

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Tyrosyl phosphorylation of the p21-activated serine-threonine kinase 1 (PAK1) has an essential role in regulating PAK1 functions in breast cancer cells. We previously demonstrated that PAK1 serves as a common node for estrogen (E2)- and prolactin (PRL)-dependent pathways. We hypothesize herein that intracellular localization of PAK1 is affected by PRL and E2 treatments differently. We demonstrate by immunocytochemical analysis that PAK1 nuclear translocation is ligand-dependent: only PRL but not E2 stimulated PAK1 nuclear translocation. Tyrosyl phosphorylation of PAK1 is essential for this nuclear translocation because phospho-tyrosyl-deficient PAK1 Y3F mutant is retained in the cytoplasm in response to PRL. We confirmed these data by Western blot analysis of subcellular fractions. In 30 min of PRL treatment, only 48% of pTyr-PAK1 is retained in the cytoplasm of PAK1 WT clone while 52% re-distributes into the nucleus and pTyr-PAK1 shuttles back to the cytoplasm by 60 min of PRL treatment. In contrast, PAK1 Y3F is retained in the cytoplasm. E2 treatment causes nuclear translocation of neither PAK1 WT nor PAK1 Y3F. Finally, we show by an in vitro kinase assay that PRL but not E2 stimulates PAK1 kinase activity in the nuclear fraction. Thus, PAK1 nuclear translocation is ligand-dependent: PRL activates PAK1 and induces translocation of activated pTyr-PAK1 into nucleus while E2 activates pTyr-PAK1 only in the cytoplasm.

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

Cited by 32 publications

References 80 publications

PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells

PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells

Filamin A: Insights into its Exact Role in Cancers

PAK1 translocates into nucleus in response to prolactin but not to estrogen

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