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

The actin-binding protein profilin-1 (Pfn1) inhibits tumor growth and yet is also required for cell proliferation and survival, an apparent paradox. We previously identified Ser-137 of Pfn1 as a phosphorylation site within the poly-l-proline (PLP) binding pocket. Here we confirm that Ser-137 phospho...

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Veröffentlicht in:The Journal of biological chemistry 2015-04, Vol.290 (14), p.9075-9086
Hauptverfasser: Diamond, Marc I., Cai, Shirong, Boudreau, Aaron, Carey, Clifton J., Lyle, Nicholas, Pappu, Rohit V., Swamidass, S. Joshua, Bissell, Mina, Piwnica-Worms, Helen, Shao, Jieya
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container_end_page 9086
container_issue 14
container_start_page 9075
container_title The Journal of biological chemistry
container_volume 290
creator Diamond, Marc I.
Cai, Shirong
Boudreau, Aaron
Carey, Clifton J.
Lyle, Nicholas
Pappu, Rohit V.
Swamidass, S. Joshua
Bissell, Mina
Piwnica-Worms, Helen
Shao, Jieya
description The actin-binding protein profilin-1 (Pfn1) inhibits tumor growth and yet is also required for cell proliferation and survival, an apparent paradox. We previously identified Ser-137 of Pfn1 as a phosphorylation site within the poly-l-proline (PLP) binding pocket. Here we confirm that Ser-137 phosphorylation disrupts Pfn1 binding to its PLP-containing ligands with little effect on actin binding. We find in mouse xenografts of breast cancer cells that mimicking Ser-137 phosphorylation abolishes cell cycle arrest and apoptotic sensitization by Pfn1 and confers a growth advantage to tumors. This indicates a previously unrecognized role of PLP binding in Pfn1 antitumor effects. Spatial restriction of Pfn1 to the nucleus or cytoplasm indicates that inhibition of tumor cell growth by Pfn1 requires its nuclear localization, and this activity is abolished by a phosphomimetic mutation on Ser-137. In contrast, cytoplasmic Pfn1 lacks inhibitory effects on tumor cell growth but rescues morphological and proliferative defects of PFN1 null mouse chondrocytes. These results help reconcile seemingly opposed cellular effects of Pfn1, provide new insights into the antitumor mechanism of Pfn1, and implicate Ser-137 phosphorylation as a potential therapeutic target for breast cancer. Background: The actin-binding protein profilin-1 is a eukaryotic protein essential for growth, with poorly understood antitumor function. Results: Profilin-1 antitumor activity requires nuclear localization and is inhibited by Ser-137 phosphorylation. Conclusion: Profilin-1 has spatially defined functions and is post-translationally regulated. Significance: Our data support a model to reconcile the seemingly oppositional functions of profilin-1 and may have implications for novel anticancer therapies.
doi_str_mv 10.1074/jbc.M114.619874
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Joshua</creatorcontrib><creatorcontrib>Bissell, Mina</creatorcontrib><creatorcontrib>Piwnica-Worms, Helen</creatorcontrib><creatorcontrib>Shao, Jieya</creatorcontrib><title>Subcellular Localization and Ser-137 Phosphorylation Regulate Tumor-suppressive Activity of Profilin-1</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The actin-binding protein profilin-1 (Pfn1) inhibits tumor growth and yet is also required for cell proliferation and survival, an apparent paradox. We previously identified Ser-137 of Pfn1 as a phosphorylation site within the poly-l-proline (PLP) binding pocket. Here we confirm that Ser-137 phosphorylation disrupts Pfn1 binding to its PLP-containing ligands with little effect on actin binding. We find in mouse xenografts of breast cancer cells that mimicking Ser-137 phosphorylation abolishes cell cycle arrest and apoptotic sensitization by Pfn1 and confers a growth advantage to tumors. 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Joshua</au><au>Bissell, Mina</au><au>Piwnica-Worms, Helen</au><au>Shao, Jieya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Subcellular Localization and Ser-137 Phosphorylation Regulate Tumor-suppressive Activity of Profilin-1</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2015-04-03</date><risdate>2015</risdate><volume>290</volume><issue>14</issue><spage>9075</spage><epage>9086</epage><pages>9075-9086</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The actin-binding protein profilin-1 (Pfn1) inhibits tumor growth and yet is also required for cell proliferation and survival, an apparent paradox. We previously identified Ser-137 of Pfn1 as a phosphorylation site within the poly-l-proline (PLP) binding pocket. Here we confirm that Ser-137 phosphorylation disrupts Pfn1 binding to its PLP-containing ligands with little effect on actin binding. We find in mouse xenografts of breast cancer cells that mimicking Ser-137 phosphorylation abolishes cell cycle arrest and apoptotic sensitization by Pfn1 and confers a growth advantage to tumors. This indicates a previously unrecognized role of PLP binding in Pfn1 antitumor effects. Spatial restriction of Pfn1 to the nucleus or cytoplasm indicates that inhibition of tumor cell growth by Pfn1 requires its nuclear localization, and this activity is abolished by a phosphomimetic mutation on Ser-137. In contrast, cytoplasmic Pfn1 lacks inhibitory effects on tumor cell growth but rescues morphological and proliferative defects of PFN1 null mouse chondrocytes. These results help reconcile seemingly opposed cellular effects of Pfn1, provide new insights into the antitumor mechanism of Pfn1, and implicate Ser-137 phosphorylation as a potential therapeutic target for breast cancer. Background: The actin-binding protein profilin-1 is a eukaryotic protein essential for growth, with poorly understood antitumor function. Results: Profilin-1 antitumor activity requires nuclear localization and is inhibited by Ser-137 phosphorylation. Conclusion: Profilin-1 has spatially defined functions and is post-translationally regulated. Significance: Our data support a model to reconcile the seemingly oppositional functions of profilin-1 and may have implications for novel anticancer therapies.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25681442</pmid><doi>10.1074/jbc.M114.619874</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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subjects Apoptosis
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer
Cell Biology
Cell Compartmentalization
Cell Line, Tumor
Genes, Tumor Suppressor
Humans
Nucleus
Phosphorylation
Profilin
Profilins - chemistry
Profilins - metabolism
Proliferation
Serine - metabolism
Subcellular Fractions - metabolism
title Subcellular Localization and Ser-137 Phosphorylation Regulate Tumor-suppressive Activity of Profilin-1
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