DYRK3 Activation, Engagement of Protein Kinase A/cAMP Response Element-binding Protein, and Modulation of Progenitor Cell Survival
DYRKs are a new family ofdual-specificity tyrosine-regulatedkinases with emerging roles in cell growth and development. Recently, we discovered that DYRK3 is expressed primarily in erythroid progenitor cells and modulates late erythropoiesis. We now describe 1) roles for the DYRK3 YTY signature moti...
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Veröffentlicht in: | The Journal of biological chemistry 2002-12, Vol.277 (49), p.47052-47060 |
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description | DYRKs are a new family ofdual-specificity tyrosine-regulatedkinases with emerging roles in cell growth and development. Recently, we discovered that DYRK3 is expressed primarily in erythroid progenitor cells and modulates late erythropoiesis. We now describe 1) roles for the DYRK3 YTY signature motif in kinase activation, 2) the coupling of DYRK3 to cAMP response element (CRE)-binding protein (CREB), and 3) effects of DYRK3 on hematopoietic progenitor cell survival. Regarding the DYRK3 kinase domain, intactness of Tyr333 (but not Tyr331) within subdomain loop VII–VIII was critical for activation. Tyr331 plus Tyr333 acidification (Tyr mutated to Glu) was constitutively activating, but kinase activity was not affected substantially by unique N- or C-terminal domains. In transfected 293 and HeLa cells, DYRK3 was discovered to efficiently stimulate CRE-luciferase expression, to activate a CREB-Gal4 fusion protein, and to promote CREB phosphorylation at Ser133. Interestingly, this CREB/CRE response was also supported (50% of wild-type activity) by a kinase-inactive DYRK3 mutant as well as a DYRK3 C-terminal region and was blocked by protein kinase A inhibitors, suggesting functional interactions between protein kinase A and DYRK3. Finally, DYRK3 expression in cytokine-dependent hematopoietic FDCW2 cells was observed to inhibit programmed cell death. Thus, primary new insight into DYRK3 kinase signaling routes, subdomain activities, and possible biofunctions is provided. |
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Recently, we discovered that DYRK3 is expressed primarily in erythroid progenitor cells and modulates late erythropoiesis. We now describe 1) roles for the DYRK3 YTY signature motif in kinase activation, 2) the coupling of DYRK3 to cAMP response element (CRE)-binding protein (CREB), and 3) effects of DYRK3 on hematopoietic progenitor cell survival. Regarding the DYRK3 kinase domain, intactness of Tyr333 (but not Tyr331) within subdomain loop VII–VIII was critical for activation. Tyr331 plus Tyr333 acidification (Tyr mutated to Glu) was constitutively activating, but kinase activity was not affected substantially by unique N- or C-terminal domains. In transfected 293 and HeLa cells, DYRK3 was discovered to efficiently stimulate CRE-luciferase expression, to activate a CREB-Gal4 fusion protein, and to promote CREB phosphorylation at Ser133. Interestingly, this CREB/CRE response was also supported (50% of wild-type activity) by a kinase-inactive DYRK3 mutant as well as a DYRK3 C-terminal region and was blocked by protein kinase A inhibitors, suggesting functional interactions between protein kinase A and DYRK3. Finally, DYRK3 expression in cytokine-dependent hematopoietic FDCW2 cells was observed to inhibit programmed cell death. Thus, primary new insight into DYRK3 kinase signaling routes, subdomain activities, and possible biofunctions is provided.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M205374200</identifier><identifier>PMID: 12356771</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Apoptosis ; Blotting, Western ; Cell Death ; Cell Line ; Cell Survival ; COS Cells ; Cyclic AMP Response Element-Binding Protein - metabolism ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Cytokines - metabolism ; DNA, Complementary - metabolism ; Dyrk Kinases ; Flow Cytometry ; Genes, Reporter ; HeLa Cells ; Hematopoietic Stem Cells - metabolism ; Humans ; Mice ; Models, Biological ; Molecular Sequence Data ; Phosphorylation ; Precipitin Tests ; Protein Binding ; Protein Serine-Threonine Kinases - metabolism ; Protein Structure, Tertiary ; Protein-Tyrosine Kinases - metabolism ; Sequence Homology, Amino Acid ; Serine - metabolism ; Signal Transduction ; Time Factors ; Transfection ; Tyrosine - chemistry</subject><ispartof>The Journal of biological chemistry, 2002-12, Vol.277 (49), p.47052-47060</ispartof><rights>2002 © 2002 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c409t-2fe6d5cc12fccffcb2fe3d29f61380a505215e9401a8df63458637880c79fda93</citedby><cites>FETCH-LOGICAL-c409t-2fe6d5cc12fccffcb2fe3d29f61380a505215e9401a8df63458637880c79fda93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27931,27932</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12356771$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Ke</creatorcontrib><creatorcontrib>Zhao, Shuqing</creatorcontrib><creatorcontrib>Karur, Vinit</creatorcontrib><creatorcontrib>Wojchowski, Don M.</creatorcontrib><title>DYRK3 Activation, Engagement of Protein Kinase A/cAMP Response Element-binding Protein, and Modulation of Progenitor Cell Survival</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>DYRKs are a new family ofdual-specificity tyrosine-regulatedkinases with emerging roles in cell growth and development. Recently, we discovered that DYRK3 is expressed primarily in erythroid progenitor cells and modulates late erythropoiesis. We now describe 1) roles for the DYRK3 YTY signature motif in kinase activation, 2) the coupling of DYRK3 to cAMP response element (CRE)-binding protein (CREB), and 3) effects of DYRK3 on hematopoietic progenitor cell survival. Regarding the DYRK3 kinase domain, intactness of Tyr333 (but not Tyr331) within subdomain loop VII–VIII was critical for activation. Tyr331 plus Tyr333 acidification (Tyr mutated to Glu) was constitutively activating, but kinase activity was not affected substantially by unique N- or C-terminal domains. In transfected 293 and HeLa cells, DYRK3 was discovered to efficiently stimulate CRE-luciferase expression, to activate a CREB-Gal4 fusion protein, and to promote CREB phosphorylation at Ser133. Interestingly, this CREB/CRE response was also supported (50% of wild-type activity) by a kinase-inactive DYRK3 mutant as well as a DYRK3 C-terminal region and was blocked by protein kinase A inhibitors, suggesting functional interactions between protein kinase A and DYRK3. Finally, DYRK3 expression in cytokine-dependent hematopoietic FDCW2 cells was observed to inhibit programmed cell death. Thus, primary new insight into DYRK3 kinase signaling routes, subdomain activities, and possible biofunctions is provided.</description><subject>Amino Acid Motifs</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Blotting, Western</subject><subject>Cell Death</subject><subject>Cell Line</subject><subject>Cell Survival</subject><subject>COS Cells</subject><subject>Cyclic AMP Response Element-Binding Protein - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Cytokines - metabolism</subject><subject>DNA, Complementary - metabolism</subject><subject>Dyrk Kinases</subject><subject>Flow Cytometry</subject><subject>Genes, Reporter</subject><subject>HeLa Cells</subject><subject>Hematopoietic Stem Cells - metabolism</subject><subject>Humans</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Molecular Sequence Data</subject><subject>Phosphorylation</subject><subject>Precipitin Tests</subject><subject>Protein Binding</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Protein Structure, Tertiary</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Sequence Homology, Amino Acid</subject><subject>Serine - metabolism</subject><subject>Signal Transduction</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Tyrosine - chemistry</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kM1v0zAYhy0EYmVw5Yh8QJyWzh9JnByrUj60VUwDJDhZjv069ZTYxU6KuPKXY9ainfDFsvW8v_enB6GXlCwpEeXlXaeXW0YqLkpGyCO0oKThBa_ot8doQQijRcuq5gw9S-mO5FO29Ck6o4xXtRB0gX6__X57xfFKT-6gJhf8Bd74XvUwgp9wsPgmhgmcx1fOqwR4dalX2xt8C2kffH5vhnuy6Jw3zvf_8AusvMHbYObhPvWU1IN3U4h4DcOAP8_xkJcOz9ETq4YEL073Ofr6bvNl_aG4_vT-43p1XeiStFPBLNSm0poyq7W1ussf3LDW1pQ3RFWkYrSCtiRUNcbWvKyamoumIVq01qiWn6M3x9x9DD9mSJMcXdK5ifIQ5iQFE5y1nGdweQR1DClFsHIf3ajiL0mJ_GtdZuvywXoeeHVKnrsRzAN-0pyB10dg5_rdTxdBdi7oHYySCSHLVpYi189Yc8Qgazg4iDJpB16DySN6kia4_1X4AywbnJw</recordid><startdate>20021206</startdate><enddate>20021206</enddate><creator>Li, Ke</creator><creator>Zhao, Shuqing</creator><creator>Karur, Vinit</creator><creator>Wojchowski, Don M.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20021206</creationdate><title>DYRK3 Activation, Engagement of Protein Kinase A/cAMP Response Element-binding Protein, and Modulation of Progenitor Cell Survival</title><author>Li, Ke ; Zhao, Shuqing ; Karur, Vinit ; Wojchowski, Don M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c409t-2fe6d5cc12fccffcb2fe3d29f61380a505215e9401a8df63458637880c79fda93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Amino Acid Motifs</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Blotting, Western</topic><topic>Cell Death</topic><topic>Cell Line</topic><topic>Cell Survival</topic><topic>COS Cells</topic><topic>Cyclic AMP Response Element-Binding Protein - metabolism</topic><topic>Cyclic AMP-Dependent Protein Kinases - metabolism</topic><topic>Cytokines - metabolism</topic><topic>DNA, Complementary - metabolism</topic><topic>Dyrk Kinases</topic><topic>Flow Cytometry</topic><topic>Genes, Reporter</topic><topic>HeLa Cells</topic><topic>Hematopoietic Stem Cells - metabolism</topic><topic>Humans</topic><topic>Mice</topic><topic>Models, Biological</topic><topic>Molecular Sequence Data</topic><topic>Phosphorylation</topic><topic>Precipitin Tests</topic><topic>Protein Binding</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Protein Structure, Tertiary</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Sequence Homology, Amino Acid</topic><topic>Serine - metabolism</topic><topic>Signal Transduction</topic><topic>Time Factors</topic><topic>Transfection</topic><topic>Tyrosine - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Ke</creatorcontrib><creatorcontrib>Zhao, Shuqing</creatorcontrib><creatorcontrib>Karur, Vinit</creatorcontrib><creatorcontrib>Wojchowski, Don M.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Ke</au><au>Zhao, Shuqing</au><au>Karur, Vinit</au><au>Wojchowski, Don M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DYRK3 Activation, Engagement of Protein Kinase A/cAMP Response Element-binding Protein, and Modulation of Progenitor Cell Survival</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2002-12-06</date><risdate>2002</risdate><volume>277</volume><issue>49</issue><spage>47052</spage><epage>47060</epage><pages>47052-47060</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>DYRKs are a new family ofdual-specificity tyrosine-regulatedkinases with emerging roles in cell growth and development. Recently, we discovered that DYRK3 is expressed primarily in erythroid progenitor cells and modulates late erythropoiesis. We now describe 1) roles for the DYRK3 YTY signature motif in kinase activation, 2) the coupling of DYRK3 to cAMP response element (CRE)-binding protein (CREB), and 3) effects of DYRK3 on hematopoietic progenitor cell survival. Regarding the DYRK3 kinase domain, intactness of Tyr333 (but not Tyr331) within subdomain loop VII–VIII was critical for activation. Tyr331 plus Tyr333 acidification (Tyr mutated to Glu) was constitutively activating, but kinase activity was not affected substantially by unique N- or C-terminal domains. In transfected 293 and HeLa cells, DYRK3 was discovered to efficiently stimulate CRE-luciferase expression, to activate a CREB-Gal4 fusion protein, and to promote CREB phosphorylation at Ser133. Interestingly, this CREB/CRE response was also supported (50% of wild-type activity) by a kinase-inactive DYRK3 mutant as well as a DYRK3 C-terminal region and was blocked by protein kinase A inhibitors, suggesting functional interactions between protein kinase A and DYRK3. Finally, DYRK3 expression in cytokine-dependent hematopoietic FDCW2 cells was observed to inhibit programmed cell death. Thus, primary new insight into DYRK3 kinase signaling routes, subdomain activities, and possible biofunctions is provided.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>12356771</pmid><doi>10.1074/jbc.M205374200</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Amino Acid Motifs Amino Acid Sequence Animals Apoptosis Blotting, Western Cell Death Cell Line Cell Survival COS Cells Cyclic AMP Response Element-Binding Protein - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism Cytokines - metabolism DNA, Complementary - metabolism Dyrk Kinases Flow Cytometry Genes, Reporter HeLa Cells Hematopoietic Stem Cells - metabolism Humans Mice Models, Biological Molecular Sequence Data Phosphorylation Precipitin Tests Protein Binding Protein Serine-Threonine Kinases - metabolism Protein Structure, Tertiary Protein-Tyrosine Kinases - metabolism Sequence Homology, Amino Acid Serine - metabolism Signal Transduction Time Factors Transfection Tyrosine - chemistry |
title | DYRK3 Activation, Engagement of Protein Kinase A/cAMP Response Element-binding Protein, and Modulation of Progenitor Cell Survival |
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