Subcellular Localization and Ser-137 Phosphorylation Regulate Tumor-suppressive Activity of Profilin-1

Diamond, Marc I.; Cai, Shirong; Boudreau, Aaron; Carey, Clifton J.; Lyle, Nicholas; Pappu, Rohit V.; Swamidass, S. Joshua; Bissell, Mina J.; Piwnica‐Worms, Helen; Shao, Jieya

doi:10.1074/jbc.m114.619874

Cited by 24 publications

(57 citation statements)

References 40 publications

(43 reference statements)

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“…Another recent report showed that PFN1 had contrasting effects on breast cancer in a context-dependent manner [ 29 ]. Other reports suggested that post-translational modifications, such as phosphorylation of PFN1 at Ser 137 or Tyr 129, could change the properties of cancer cells [ 30 – 32 ]. Hence, the roles of profilin in various cancers need to be further clarified.…”

Section: Introductionmentioning

confidence: 99%

PFN2, a novel marker of unfavorable prognosis, is a potential therapeutic target involved in esophageal squamous cell carcinoma

Cui

Zhang

et al. 2016

J Transl Med

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BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most aggressively malignant tumors with dismal prognosis. Profilin 2 (PFN2) is an actin-binding protein that regulates the dynamics of actin polymerization and plays a key role in cell motility. Recently, PFN2 have emerged as significant regulators of cancer processes. However, the clinical significance and biological function of PFN2 in ESCC remain unclear.MethodsPFN2 protein expression was validated by immunohistochemistry (IHC) on tissue microarray from Chinese Han and Kazakh populations with ESCC. The associations among PFN2 expression, clinicopathological features, and prognosis of ESCC were analyzed. The effects on cell proliferation, invasion and migration were examined using MTT and Transwell assays. Markers of epithelial–mesenchymal transition (EMT) were detected by Western blot analysis.ResultsCompared with normal esophageal epithelium (NEE), PFN2 protein expression was markedly increased in low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and ESCC, increased gradually from LGIN to ESCC, and finally reached high grade in HGIN in the Han population. Similarly, PFN2 protein was more overexpressed in ESCC than in NEE in the Kazakh population. The results of Western blot analysis also showed that PFN2 expression was significantly higher in the ESCC tissue than in a matched adjacent non-cancerous tissue. PFN2 expression was positively correlated with invasion depth and lymph node metastasis. High PFN2 expression was significantly correlated with short overall survival (OS) (P = 0.023). Cox regression analysis revealed that PFN2 expression was an independent prognostic factor for poor OS in ESCC. Downregulation of PFN2 inhibited, rather than proliferated, cell invasion and migration, as well as induced an EMT phenotype, including increased expression of epithelial marker E-cadherin, decreased mesenchymal marker Vimentin, Snail, Slug and ZEB1, and morphological changes in ESCC cells in vitro.ConclusionsOur findings demonstrate that PFN2 has a novel role in promoting ESCC progression and metastasis and portending a poor prognosis, indicating that PFN2 could act as an early biomarker of high-risk population. Targeting PFN2 may offer a promising therapeutic strategy for ESCC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0884-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

PFN2, a novel marker of unfavorable prognosis, is a potential therapeutic target involved in esophageal squamous cell carcinoma

Cui

Zhang

et al. 2016

J Transl Med

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“…This phosphorylation disrupt the binding to proline rich domain (PRD) containing proteins and favors the localization of Pfn1 in the nucleus which appears to be necessary for its role in cell cycle arrest and proliferation. 5 In the cytoplasm, increased Pfn1 level promotes the formation of actin cables following the interaction of profilin-actin with formins and Ena-Vasp rather than branched filament networks by Arp2/3 complex. 6 This behavior is consistent with the stabilization of adherens junctions as proposed in Jiang et al On the other hand, phosphorylation of Pfn1 at S137 would inhibit its interaction with formin and Ena-Vasp and prevent Pfn1 effect on adherens junction.…”

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confidence: 99%

Profilin-1 mediated cell-cycle arrest: searching for drug targets

Moens

Coumans

2015

Cell Cycle

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“…Previousinvestigationshavedemonstratedthatthephosphorylation of proteins contributes to their subcellular localization (21,22). Given that silkworm BR-C is a member of the nuclear receptor family of transcription factors, we examined whether PKA-mediated BR-C phosphorylation at Ser-186 is required for…”

Section: Pka-mediated Br-c Phosphorylation At Ser-186 Did Not Affect mentioning

confidence: 99%

Protein kinase A-mediated phosphorylation of the Broad-Complex transcription factor in silkworm suppresses its transcriptional activity

Qian

Gang

Zhang

et al. 2017

Journal of Biological Chemistry

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The insect-specific transcription factor Broad-Complex (BR-C) is transcriptionally activated by the steroid 20-hydroxyecdysone (20E) and regulates the expression of many target genes involved in insect growth and development. However, although the transcriptional regulation of BR-C proteins has been well studied, how BR-C is regulated at post-transcription and -translation levels is poorly understood. To this end, using liquid chromatography-tandem mass spectrometry analysis, we identified residue Ser-186 as a phosphorylation site of BR-C in silkworm. Site-directed mutagenesis and treatment with specific kinase activators and inhibitors indicated that the Ser-186 residue in silkworm BR-C is phosphorylated by protein kinase A (PKA). Immunostaining assays disclosed that PKA-mediated phosphorylation of silkworm BR-C has no effect on its nuclear import. However, luciferase reporter analysis, electrophoretic mobility shift assays, and chromatin immunoprecipitation revealed that the PKA phosphorylation event suppresses the transcriptional activation of silkworm BR-C target genes and that this inhibition was caused by repression of BR-C binding to its DNA targets. Of note, both and experiments disclosed that a continuous 20E signal inhibits the PKA-mediated BR-C phosphorylation and also the cAMP/PKA pathway, indicating that 20E's inhibitory effect on PKA-mediated phosphorylation of silkworm BR-C contributes to maintaining BR-C transcriptional activity. In conclusion, our findings indicate that PKA-mediated phosphorylation inhibits silkworm BR-C activity by interfering with its binding to DNA and that 20E signaling relieves PKA-mediated phosphorylation of BR-C, thereby maintaining its transcriptional activity.

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Subcellular Localization and Ser-137 Phosphorylation Regulate Tumor-suppressive Activity of Profilin-1

Cited by 24 publications

References 40 publications

PFN2, a novel marker of unfavorable prognosis, is a potential therapeutic target involved in esophageal squamous cell carcinoma

PFN2, a novel marker of unfavorable prognosis, is a potential therapeutic target involved in esophageal squamous cell carcinoma

Profilin-1 mediated cell-cycle arrest: searching for drug targets

Protein kinase A-mediated phosphorylation of the Broad-Complex transcription factor in silkworm suppresses its transcriptional activity

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