Tyrosine Phosphorylation of Protein Kinase D in the Pleckstrin Homology Domain Leads to Activation
Protein kinase D (PKD) is a member of the AGC family of Ser/Thr kinases and is distantly related to protein kinase C (PKC). Formerly known as PKCμ, PKD contains protein domains not found in conventional PKC isoforms. A functional pleckstrin homology (PH) domain is critical for the regulation of PKD...
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| Veröffentlicht in: | The Journal of biological chemistry 2003-05, Vol.278 (20), p.17969-17976 |
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| container_title | The Journal of biological chemistry |
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| creator | Storz, Peter Döppler, Heike Johannes, Franz-Josef Toker, Alex |
| description | Protein kinase D (PKD) is a member of the AGC family of Ser/Thr kinases and is distantly related to protein kinase C (PKC).
Formerly known as PKCμ, PKD contains protein domains not found in conventional PKC isoforms. A functional pleckstrin homology
(PH) domain is critical for the regulation of PKD activity. Here we report that PKD is tyrosine-phosphorylated within the
PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine
kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine
phosphorylation sites (Tyr 432 , Tyr 463 , and Tyr 502 ), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr 463 ) leads to PKD activation. By using a phospho-specific antibody, we show that Abl directly phosphorylates PKD at Tyr 463 in vitro , and in cells phosphorylation of this site is sufficient to mediate full activation of PKD. Mutation of the other two sites,
Tyr 432 and Tyr 502 , had no significant influence on PKD activity. These data reveal a tyrosine phosphorylation-dependent activation mechanism
for PKD and suggest that this event contributes to the release of the autoinhibitory PKD PH domain leading to kinase activation
and downstream responses. |
| doi_str_mv | 10.1074/jbc.M213224200 |
| format | Article |
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Formerly known as PKCμ, PKD contains protein domains not found in conventional PKC isoforms. A functional pleckstrin homology
(PH) domain is critical for the regulation of PKD activity. Here we report that PKD is tyrosine-phosphorylated within the
PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine
kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine
phosphorylation sites (Tyr 432 , Tyr 463 , and Tyr 502 ), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr 463 ) leads to PKD activation. By using a phospho-specific antibody, we show that Abl directly phosphorylates PKD at Tyr 463 in vitro , and in cells phosphorylation of this site is sufficient to mediate full activation of PKD. Mutation of the other two sites,
Tyr 432 and Tyr 502 , had no significant influence on PKD activity. These data reveal a tyrosine phosphorylation-dependent activation mechanism
for PKD and suggest that this event contributes to the release of the autoinhibitory PKD PH domain leading to kinase activation
and downstream responses.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M213224200</identifier><identifier>PMID: 12637538</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Amino Acid Sequence ; Blood Proteins - chemistry ; Blood Proteins - metabolism ; Blotting, Western ; DNA - metabolism ; Enzyme Activation ; Enzyme Inhibitors - pharmacology ; HeLa Cells ; Humans ; Hydrogen Peroxide - pharmacology ; Immunoblotting ; Molecular Sequence Data ; Mutation ; Phosphoproteins - chemistry ; Phosphoproteins - metabolism ; Phosphorylation ; Precipitin Tests ; Protein Kinase C - metabolism ; Protein Structure, Tertiary ; Recombinant Proteins - metabolism ; Signal Transduction ; Time Factors ; Transfection ; Tyrosine - genetics ; Tyrosine - metabolism ; Vanadates - pharmacology</subject><ispartof>The Journal of biological chemistry, 2003-05, Vol.278 (20), p.17969-17976</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-e68aa8131da2d3080ec888df44496edb095551d87e8866ea4b554e3e67be3f413</citedby><cites>FETCH-LOGICAL-c426t-e68aa8131da2d3080ec888df44496edb095551d87e8866ea4b554e3e67be3f413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12637538$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Storz, Peter</creatorcontrib><creatorcontrib>Döppler, Heike</creatorcontrib><creatorcontrib>Johannes, Franz-Josef</creatorcontrib><creatorcontrib>Toker, Alex</creatorcontrib><title>Tyrosine Phosphorylation of Protein Kinase D in the Pleckstrin Homology Domain Leads to Activation</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Protein kinase D (PKD) is a member of the AGC family of Ser/Thr kinases and is distantly related to protein kinase C (PKC).
Formerly known as PKCμ, PKD contains protein domains not found in conventional PKC isoforms. A functional pleckstrin homology
(PH) domain is critical for the regulation of PKD activity. Here we report that PKD is tyrosine-phosphorylated within the
PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine
kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine
phosphorylation sites (Tyr 432 , Tyr 463 , and Tyr 502 ), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr 463 ) leads to PKD activation. By using a phospho-specific antibody, we show that Abl directly phosphorylates PKD at Tyr 463 in vitro , and in cells phosphorylation of this site is sufficient to mediate full activation of PKD. Mutation of the other two sites,
Tyr 432 and Tyr 502 , had no significant influence on PKD activity. These data reveal a tyrosine phosphorylation-dependent activation mechanism
for PKD and suggest that this event contributes to the release of the autoinhibitory PKD PH domain leading to kinase activation
and downstream responses.</description><subject>Amino Acid Sequence</subject><subject>Blood Proteins - chemistry</subject><subject>Blood Proteins - metabolism</subject><subject>Blotting, Western</subject><subject>DNA - metabolism</subject><subject>Enzyme Activation</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>Immunoblotting</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Phosphoproteins - chemistry</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation</subject><subject>Precipitin Tests</subject><subject>Protein Kinase C - metabolism</subject><subject>Protein Structure, Tertiary</subject><subject>Recombinant Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Tyrosine - genetics</subject><subject>Tyrosine - metabolism</subject><subject>Vanadates - pharmacology</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkL1PwzAQxS0EoqWwMiIPrCn-iuOMVQsUUUSHIrFZTnJpXJK4igMo_z2GVuKWuyf93pPuIXRNyZSSRNztsnz6wihnTDBCTtCYEsUjHtP3UzQmhNEoZbEaoQvvdySMSOk5GlEmeRJzNUbZZuicty3gdeX8vnLdUJveuha7Eq8714Nt8bNtjQe8wOHuq4DWkH_4vgty6RpXu-2AF64xQa_AFB73Ds_y3n79JV2is9LUHq6Oe4LeHu4382W0en18ms9WUS6Y7COQyhhFOS0MKzhRBHKlVFEKIVIJRUbSOI5poRJQSkowIotjARxkkgEvBeUTND3k5uEj30Gp951tTDdoSvRvWTqUpf_LCoabg2H_mTVQ_OPHdgJwewAqu62-bQc6sy6voNEsUZqF1CSVKf8BvSxx6A</recordid><startdate>20030516</startdate><enddate>20030516</enddate><creator>Storz, Peter</creator><creator>Döppler, Heike</creator><creator>Johannes, Franz-Josef</creator><creator>Toker, Alex</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20030516</creationdate><title>Tyrosine Phosphorylation of Protein Kinase D in the Pleckstrin Homology Domain Leads to Activation</title><author>Storz, Peter ; Döppler, Heike ; Johannes, Franz-Josef ; Toker, Alex</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-e68aa8131da2d3080ec888df44496edb095551d87e8866ea4b554e3e67be3f413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Amino Acid Sequence</topic><topic>Blood Proteins - chemistry</topic><topic>Blood Proteins - metabolism</topic><topic>Blotting, Western</topic><topic>DNA - metabolism</topic><topic>Enzyme Activation</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Hydrogen Peroxide - pharmacology</topic><topic>Immunoblotting</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Phosphoproteins - chemistry</topic><topic>Phosphoproteins - metabolism</topic><topic>Phosphorylation</topic><topic>Precipitin Tests</topic><topic>Protein Kinase C - metabolism</topic><topic>Protein Structure, Tertiary</topic><topic>Recombinant Proteins - metabolism</topic><topic>Signal Transduction</topic><topic>Time Factors</topic><topic>Transfection</topic><topic>Tyrosine - genetics</topic><topic>Tyrosine - metabolism</topic><topic>Vanadates - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Storz, Peter</creatorcontrib><creatorcontrib>Döppler, Heike</creatorcontrib><creatorcontrib>Johannes, Franz-Josef</creatorcontrib><creatorcontrib>Toker, Alex</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Storz, Peter</au><au>Döppler, Heike</au><au>Johannes, Franz-Josef</au><au>Toker, Alex</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tyrosine Phosphorylation of Protein Kinase D in the Pleckstrin Homology Domain Leads to Activation</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2003-05-16</date><risdate>2003</risdate><volume>278</volume><issue>20</issue><spage>17969</spage><epage>17976</epage><pages>17969-17976</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Protein kinase D (PKD) is a member of the AGC family of Ser/Thr kinases and is distantly related to protein kinase C (PKC).
Formerly known as PKCμ, PKD contains protein domains not found in conventional PKC isoforms. A functional pleckstrin homology
(PH) domain is critical for the regulation of PKD activity. Here we report that PKD is tyrosine-phosphorylated within the
PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine
kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine
phosphorylation sites (Tyr 432 , Tyr 463 , and Tyr 502 ), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr 463 ) leads to PKD activation. By using a phospho-specific antibody, we show that Abl directly phosphorylates PKD at Tyr 463 in vitro , and in cells phosphorylation of this site is sufficient to mediate full activation of PKD. Mutation of the other two sites,
Tyr 432 and Tyr 502 , had no significant influence on PKD activity. These data reveal a tyrosine phosphorylation-dependent activation mechanism
for PKD and suggest that this event contributes to the release of the autoinhibitory PKD PH domain leading to kinase activation
and downstream responses.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>12637538</pmid><doi>10.1074/jbc.M213224200</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2003-05, Vol.278 (20), p.17969-17976 |
| issn | 0021-9258 1083-351X |
| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Amino Acid Sequence Blood Proteins - chemistry Blood Proteins - metabolism Blotting, Western DNA - metabolism Enzyme Activation Enzyme Inhibitors - pharmacology HeLa Cells Humans Hydrogen Peroxide - pharmacology Immunoblotting Molecular Sequence Data Mutation Phosphoproteins - chemistry Phosphoproteins - metabolism Phosphorylation Precipitin Tests Protein Kinase C - metabolism Protein Structure, Tertiary Recombinant Proteins - metabolism Signal Transduction Time Factors Transfection Tyrosine - genetics Tyrosine - metabolism Vanadates - pharmacology |
| title | Tyrosine Phosphorylation of Protein Kinase D in the Pleckstrin Homology Domain Leads to Activation |
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