Links to Exploration step
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer</title><author><name sortKey="Chellappa, Karthikeyani" sort="Chellappa, Karthikeyani" uniqKey="Chellappa K" first="Karthikeyani" last="Chellappa">Karthikeyani Chellappa</name><affiliation><nlm:aff id="aff1">Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521;</nlm:aff></affiliation></author><author><name sortKey="Jankova, Lucy" sort="Jankova, Lucy" uniqKey="Jankova L" first="Lucy" last="Jankova">Lucy Jankova</name><affiliation><nlm:aff id="aff2">Cancer Pharmacology Unit, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia;</nlm:aff></affiliation></author><author><name sortKey="Schnabl, Jake M" sort="Schnabl, Jake M" uniqKey="Schnabl J" first="Jake M." last="Schnabl">Jake M. Schnabl</name><affiliation><nlm:aff id="aff1">Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521;</nlm:aff></affiliation></author><author><name sortKey="Pan, Songqin" sort="Pan, Songqin" uniqKey="Pan S" first="Songqin" last="Pan">Songqin Pan</name><affiliation><nlm:aff id="aff3"> W. M. Keck Proteomics Laboratory, Institute for Integrative Genome Biology, University of California, Riverside, CA 92521;</nlm:aff></affiliation></author><author><name sortKey="Brelivet, Yann" sort="Brelivet, Yann" uniqKey="Brelivet Y" first="Yann" last="Brelivet">Yann Brelivet</name><affiliation><nlm:aff id="aff4">Département de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France;</nlm:aff></affiliation></author><author><name sortKey="Fung, Caroline L S" sort="Fung, Caroline L S" uniqKey="Fung C" first="Caroline L-S." last="Fung">Caroline L-S. Fung</name><affiliation><nlm:aff id="aff5">Department of Anatomical Pathology,</nlm:aff></affiliation></author><author><name sortKey="Chan, Charles" sort="Chan, Charles" uniqKey="Chan C" first="Charles" last="Chan">Charles Chan</name><affiliation><nlm:aff id="aff5">Department of Anatomical Pathology,</nlm:aff></affiliation></author><author><name sortKey="Dent, Owen F" sort="Dent, Owen F" uniqKey="Dent O" first="Owen F." last="Dent">Owen F. Dent</name><affiliation><nlm:aff wicri:cut="; and" id="aff6">Department of Colorectal Surgery, Concord Hospital</nlm:aff></affiliation></author><author><name sortKey="Clarke, Stephen J" sort="Clarke, Stephen J" uniqKey="Clarke S" first="Stephen J." last="Clarke">Stephen J. Clarke</name><affiliation><nlm:aff id="aff7">Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Robertson, Graham R" sort="Robertson, Graham R" uniqKey="Robertson G" first="Graham R." last="Robertson">Graham R. Robertson</name><affiliation><nlm:aff id="aff2">Cancer Pharmacology Unit, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia;</nlm:aff></affiliation></author><author><name sortKey="Sladek, Frances M" sort="Sladek, Frances M" uniqKey="Sladek F" first="Frances M." last="Sladek">Frances M. Sladek</name><affiliation><nlm:aff id="aff1">Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22308320</idno><idno type="pmc">3289305</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289305</idno><idno type="RBID">PMC:3289305</idno><idno type="doi">10.1073/pnas.1106799109</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001B61</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001B61</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer</title><author><name sortKey="Chellappa, Karthikeyani" sort="Chellappa, Karthikeyani" uniqKey="Chellappa K" first="Karthikeyani" last="Chellappa">Karthikeyani Chellappa</name><affiliation><nlm:aff id="aff1">Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521;</nlm:aff></affiliation></author><author><name sortKey="Jankova, Lucy" sort="Jankova, Lucy" uniqKey="Jankova L" first="Lucy" last="Jankova">Lucy Jankova</name><affiliation><nlm:aff id="aff2">Cancer Pharmacology Unit, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia;</nlm:aff></affiliation></author><author><name sortKey="Schnabl, Jake M" sort="Schnabl, Jake M" uniqKey="Schnabl J" first="Jake M." last="Schnabl">Jake M. Schnabl</name><affiliation><nlm:aff id="aff1">Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521;</nlm:aff></affiliation></author><author><name sortKey="Pan, Songqin" sort="Pan, Songqin" uniqKey="Pan S" first="Songqin" last="Pan">Songqin Pan</name><affiliation><nlm:aff id="aff3"> W. M. Keck Proteomics Laboratory, Institute for Integrative Genome Biology, University of California, Riverside, CA 92521;</nlm:aff></affiliation></author><author><name sortKey="Brelivet, Yann" sort="Brelivet, Yann" uniqKey="Brelivet Y" first="Yann" last="Brelivet">Yann Brelivet</name><affiliation><nlm:aff id="aff4">Département de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France;</nlm:aff></affiliation></author><author><name sortKey="Fung, Caroline L S" sort="Fung, Caroline L S" uniqKey="Fung C" first="Caroline L-S." last="Fung">Caroline L-S. Fung</name><affiliation><nlm:aff id="aff5">Department of Anatomical Pathology,</nlm:aff></affiliation></author><author><name sortKey="Chan, Charles" sort="Chan, Charles" uniqKey="Chan C" first="Charles" last="Chan">Charles Chan</name><affiliation><nlm:aff id="aff5">Department of Anatomical Pathology,</nlm:aff></affiliation></author><author><name sortKey="Dent, Owen F" sort="Dent, Owen F" uniqKey="Dent O" first="Owen F." last="Dent">Owen F. Dent</name><affiliation><nlm:aff wicri:cut="; and" id="aff6">Department of Colorectal Surgery, Concord Hospital</nlm:aff></affiliation></author><author><name sortKey="Clarke, Stephen J" sort="Clarke, Stephen J" uniqKey="Clarke S" first="Stephen J." last="Clarke">Stephen J. Clarke</name><affiliation><nlm:aff id="aff7">Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Robertson, Graham R" sort="Robertson, Graham R" uniqKey="Robertson G" first="Graham R." last="Robertson">Graham R. Robertson</name><affiliation><nlm:aff id="aff2">Cancer Pharmacology Unit, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia;</nlm:aff></affiliation></author><author><name sortKey="Sladek, Frances M" sort="Sladek, Frances M" uniqKey="Sladek F" first="Frances M." last="Sladek">Frances M. Sladek</name><affiliation><nlm:aff id="aff1">Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Src tyrosine kinase has long been implicated in colon cancer but much remains to be learned about its substrates. The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) has just recently been implicated in colon cancer but its role is poorly defined. Here we show that c-Src phosphorylates human HNF4α on three tyrosines in an interdependent and isoform-specific fashion. The initial phosphorylation site is a Tyr residue (Y14) present in the N-terminal A/B domain of P1- but not P2-driven HNF4α. Phospho-Y14 interacts with the Src SH2 domain, leading to the phosphorylation of two additional tyrosines in the ligand binding domain (LBD) in P1-HNF4α. Phosphomimetic mutants in the LBD decrease P1-HNF4α protein stability, nuclear localization and transactivation function. Immunohistochemical analysis of approximately 450 human colon cancer specimens (Stage III) reveals that P1-HNF4α is either lost or localized in the cytoplasm in approximately 80% of tumors, and that staining for active Src correlates with those events in a subset of samples. Finally, three SNPs in the human HNF4α protein, two of which are in the HNF4α F domain that interacts with the Src SH3 domain, increase phosphorylation by Src and decrease HNF4α protein stability and function, suggesting that individuals with those variants may be more susceptible to Src-mediated effects. This newly identified interaction between Src kinase and HNF4α has important implications for colon and other cancers.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22308320</article-id><article-id pub-id-type="pmc">3289305</article-id><article-id pub-id-type="publisher-id">201106799</article-id><article-id pub-id-type="doi">10.1073/pnas.1106799109</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Biochemistry</subject></subj-group></subj-group></article-categories><title-group><article-title>Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chellappa</surname><given-names>Karthikeyani</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jankova</surname><given-names>Lucy</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schnabl</surname><given-names>Jake M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pan</surname><given-names>Songqin</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brelivet</surname><given-names>Yann</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fung</surname><given-names>Caroline L-S.</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chan</surname><given-names>Charles</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dent</surname><given-names>Owen F.</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Clarke</surname><given-names>Stephen J.</given-names></name><xref ref-type="aff" rid="aff7"><sup>g</sup></xref></contrib><contrib contrib-type="author"><name><surname>Robertson</surname><given-names>Graham R.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sladek</surname><given-names>Frances M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><aff id="aff1"><label>a</label>Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521;</aff><aff id="aff2"><label>b</label>Cancer Pharmacology Unit, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia;</aff><aff id="aff3"><label>c</label> W. M. Keck Proteomics Laboratory, Institute for Integrative Genome Biology, University of California, Riverside, CA 92521;</aff><aff id="aff4"><label>d</label>Département de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France;</aff><aff id="aff5"><label>e</label>Department of Anatomical Pathology,</aff><aff id="aff6"><label>f</label>Department of Colorectal Surgery, Concord Hospital; and</aff><aff id="aff7"><label>g</label>Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia</aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence should be addressed. E-mail: <email>frances.sladek@ucr.edu</email>.</corresp><fn fn-type="edited-by"><p>Edited by Tony Hunter, The Salk Institute for Biological Studies, La Jolla, CA, and approved December 15, 2011 (received for review April 28, 2011)</p></fn><fn fn-type="participating-researchers"><p>Author contributions: K.C., G.R.R., and F.M.S. designed research; K.C., L.J., S.P., and G.R.R. performed research; Y.B. performed computational modeling; K.C., J.M.S., and S.J.C. contributed new reagents/analytic tools; K.C., L.J., S.P., C.L.-S.F., C.C., O.F.D., G.R.R., and F.M.S. analyzed data; and K.C. and F.M.S. wrote the paper.</p></fn></author-notes><pub-date pub-type="ppub"><day>14</day><month>2</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>30</day><month>1</month><year>2012</year></pub-date><volume>109</volume><issue>7</issue><fpage>2302</fpage><lpage>2307</lpage><page-range>2302-2307</page-range><self-uri content-type="pdf" xlink:type="simple" xlink:href="pnas.1106799109.pdf"></self-uri><abstract><p>Src tyrosine kinase has long been implicated in colon cancer but much remains to be learned about its substrates. The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) has just recently been implicated in colon cancer but its role is poorly defined. Here we show that c-Src phosphorylates human HNF4α on three tyrosines in an interdependent and isoform-specific fashion. The initial phosphorylation site is a Tyr residue (Y14) present in the N-terminal A/B domain of P1- but not P2-driven HNF4α. Phospho-Y14 interacts with the Src SH2 domain, leading to the phosphorylation of two additional tyrosines in the ligand binding domain (LBD) in P1-HNF4α. Phosphomimetic mutants in the LBD decrease P1-HNF4α protein stability, nuclear localization and transactivation function. Immunohistochemical analysis of approximately 450 human colon cancer specimens (Stage III) reveals that P1-HNF4α is either lost or localized in the cytoplasm in approximately 80% of tumors, and that staining for active Src correlates with those events in a subset of samples. Finally, three SNPs in the human HNF4α protein, two of which are in the HNF4α F domain that interacts with the Src SH3 domain, increase phosphorylation by Src and decrease HNF4α protein stability and function, suggesting that individuals with those variants may be more susceptible to Src-mediated effects. This newly identified interaction between Src kinase and HNF4α has important implications for colon and other cancers.</p></abstract><kwd-group><kwd>HNF4 isoforms</kwd><kwd>SH2 SH3 domain</kwd><kwd>SNP</kwd><kwd>Src kinase</kwd><kwd>tyrosine phosphorylation</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001B610 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 001B610 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Asie
|area= AustralieFrV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé=
|texte=
}}
| This area was generated with Dilib version V0.6.33. |  |