The Role of Focal Adhesion Kinase-Phosphatidylinositol 3-Kinase-Akt Signaling in Hepatic Stellate Cell Proliferation and Type I Collagen Expression
Following a fibrogenic stimulus, the hepatic stellate cell (HSC) undergoes a complex activation process associated with increased cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is activated by pl...
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| Veröffentlicht in: | The Journal of biological chemistry 2003-03, Vol.278 (10), p.8083-8090 |
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| container_title | The Journal of biological chemistry |
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| creator | Reif, Shimon Lang, Alon Lindquist, Jeffery N Yata, Yutaka Gabele, Erwin Scanga, Andrew Brenner, David A Rippe, Richard A |
| description | Following a fibrogenic stimulus, the hepatic stellate cell (HSC) undergoes a complex activation process associated with increased
cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase
(PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several cell types. We investigated
the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, cell attachment,
and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor
of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative
forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation,
did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative
effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and
inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, cell attachment, and PDGF-induced
cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K,
and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway. |
| doi_str_mv | 10.1074/jbc.M212927200 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_18682196</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>18682196</sourcerecordid><originalsourceid>FETCH-LOGICAL-c501t-ea660011ffcf99c7011666772f96ad7e16bcc7dec4ee4f8684c3678c4c7be51c3</originalsourceid><addsrcrecordid>eNpFkUFr3DAQhUVJaLZprz0GQaA3bzSyLdnHZUma0JSEZgu9CVkerZV4LUfy0u7vyB-ull3IXGbgffNG6BHyFdgcmCyunhsz_8mB11xyxj6QGbAqz_IS_pyQGWMcspqX1Rn5FOMzS1XU8JGcAS8ZlwAz8rbqkP7yPVJv6Y03uqeLtsPo_EB_uEFHzB47H8dOT67d9W7w0U2-p3l2VBcvE31y60EnbU3dQG9xTKyhTxP2vZ6QLlOnj8H3zmJIUnLWQ0tXuxHpHV36RK1xoNf_xoBxf_gzObW6j_jl2M_J75vr1fI2u3_4frdc3GemZDBlqIVgDMBaY-vayDQKIaTktha6lQiiMUa2aArEwlaiKkwuZGUKIxssweTn5NvBdwz-dYtxUhsXzf7VA_ptVJB2ONQigfMDaIKPMaBVY3AbHXYKmNrHoFIM6j2GtHBxdN42G2zf8eO_J-DyAHRu3f11AVXjvOlwo7is9q5VijH_DzvxkMI</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>18682196</pqid></control><display><type>article</type><title>The Role of Focal Adhesion Kinase-Phosphatidylinositol 3-Kinase-Akt Signaling in Hepatic Stellate Cell Proliferation and Type I Collagen Expression</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Reif, Shimon ; Lang, Alon ; Lindquist, Jeffery N ; Yata, Yutaka ; Gabele, Erwin ; Scanga, Andrew ; Brenner, David A ; Rippe, Richard A</creator><creatorcontrib>Reif, Shimon ; Lang, Alon ; Lindquist, Jeffery N ; Yata, Yutaka ; Gabele, Erwin ; Scanga, Andrew ; Brenner, David A ; Rippe, Richard A</creatorcontrib><description>Following a fibrogenic stimulus, the hepatic stellate cell (HSC) undergoes a complex activation process associated with increased
cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase
(PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several cell types. We investigated
the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, cell attachment,
and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor
of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative
forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation,
did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative
effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and
inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, cell attachment, and PDGF-induced
cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K,
and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M212927200</identifier><identifier>PMID: 12502711</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Animals ; Cell Adhesion ; Cell Division ; Cell Movement ; Cells, Cultured ; Chromones - pharmacology ; Collagen Type I - genetics ; Collagen Type I - metabolism ; Enzyme Inhibitors - pharmacology ; Focal Adhesion Kinase 1 ; Focal Adhesion Protein-Tyrosine Kinases ; Gene Expression Regulation - drug effects ; Liver - cytology ; Liver - drug effects ; Liver - enzymology ; Liver - metabolism ; Morpholines - pharmacology ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation ; Platelet-Derived Growth Factor - pharmacology ; Protein-Serine-Threonine Kinases ; Protein-Tyrosine Kinases - metabolism ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-akt ; Rats ; Rats, Sprague-Dawley ; RNA, Messenger - genetics ; Signal Transduction ; Transforming Growth Factor beta - physiology</subject><ispartof>The Journal of biological chemistry, 2003-03, Vol.278 (10), p.8083-8090</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c501t-ea660011ffcf99c7011666772f96ad7e16bcc7dec4ee4f8684c3678c4c7be51c3</citedby><cites>FETCH-LOGICAL-c501t-ea660011ffcf99c7011666772f96ad7e16bcc7dec4ee4f8684c3678c4c7be51c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12502711$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Reif, Shimon</creatorcontrib><creatorcontrib>Lang, Alon</creatorcontrib><creatorcontrib>Lindquist, Jeffery N</creatorcontrib><creatorcontrib>Yata, Yutaka</creatorcontrib><creatorcontrib>Gabele, Erwin</creatorcontrib><creatorcontrib>Scanga, Andrew</creatorcontrib><creatorcontrib>Brenner, David A</creatorcontrib><creatorcontrib>Rippe, Richard A</creatorcontrib><title>The Role of Focal Adhesion Kinase-Phosphatidylinositol 3-Kinase-Akt Signaling in Hepatic Stellate Cell Proliferation and Type I Collagen Expression</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Following a fibrogenic stimulus, the hepatic stellate cell (HSC) undergoes a complex activation process associated with increased
cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase
(PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several cell types. We investigated
the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, cell attachment,
and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor
of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative
forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation,
did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative
effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and
inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, cell attachment, and PDGF-induced
cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K,
and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.</description><subject>Animals</subject><subject>Cell Adhesion</subject><subject>Cell Division</subject><subject>Cell Movement</subject><subject>Cells, Cultured</subject><subject>Chromones - pharmacology</subject><subject>Collagen Type I - genetics</subject><subject>Collagen Type I - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Focal Adhesion Kinase 1</subject><subject>Focal Adhesion Protein-Tyrosine Kinases</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Liver - cytology</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Liver - metabolism</subject><subject>Morpholines - pharmacology</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoinositide-3 Kinase Inhibitors</subject><subject>Phosphorylation</subject><subject>Platelet-Derived Growth Factor - pharmacology</subject><subject>Protein-Serine-Threonine Kinases</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>RNA, Messenger - genetics</subject><subject>Signal Transduction</subject><subject>Transforming Growth Factor beta - physiology</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>eNpFkUFr3DAQhUVJaLZprz0GQaA3bzSyLdnHZUma0JSEZgu9CVkerZV4LUfy0u7vyB-ull3IXGbgffNG6BHyFdgcmCyunhsz_8mB11xyxj6QGbAqz_IS_pyQGWMcspqX1Rn5FOMzS1XU8JGcAS8ZlwAz8rbqkP7yPVJv6Y03uqeLtsPo_EB_uEFHzB47H8dOT67d9W7w0U2-p3l2VBcvE31y60EnbU3dQG9xTKyhTxP2vZ6QLlOnj8H3zmJIUnLWQ0tXuxHpHV36RK1xoNf_xoBxf_gzObW6j_jl2M_J75vr1fI2u3_4frdc3GemZDBlqIVgDMBaY-vayDQKIaTktha6lQiiMUa2aArEwlaiKkwuZGUKIxssweTn5NvBdwz-dYtxUhsXzf7VA_ptVJB2ONQigfMDaIKPMaBVY3AbHXYKmNrHoFIM6j2GtHBxdN42G2zf8eO_J-DyAHRu3f11AVXjvOlwo7is9q5VijH_DzvxkMI</recordid><startdate>20030307</startdate><enddate>20030307</enddate><creator>Reif, Shimon</creator><creator>Lang, Alon</creator><creator>Lindquist, Jeffery N</creator><creator>Yata, Yutaka</creator><creator>Gabele, Erwin</creator><creator>Scanga, Andrew</creator><creator>Brenner, David A</creator><creator>Rippe, Richard A</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><scope>7TM</scope></search><sort><creationdate>20030307</creationdate><title>The Role of Focal Adhesion Kinase-Phosphatidylinositol 3-Kinase-Akt Signaling in Hepatic Stellate Cell Proliferation and Type I Collagen Expression</title><author>Reif, Shimon ; Lang, Alon ; Lindquist, Jeffery N ; Yata, Yutaka ; Gabele, Erwin ; Scanga, Andrew ; Brenner, David A ; Rippe, Richard A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c501t-ea660011ffcf99c7011666772f96ad7e16bcc7dec4ee4f8684c3678c4c7be51c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Cell Adhesion</topic><topic>Cell Division</topic><topic>Cell Movement</topic><topic>Cells, Cultured</topic><topic>Chromones - pharmacology</topic><topic>Collagen Type I - genetics</topic><topic>Collagen Type I - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Focal Adhesion Kinase 1</topic><topic>Focal Adhesion Protein-Tyrosine Kinases</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Liver - cytology</topic><topic>Liver - drug effects</topic><topic>Liver - enzymology</topic><topic>Liver - metabolism</topic><topic>Morpholines - pharmacology</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoinositide-3 Kinase Inhibitors</topic><topic>Phosphorylation</topic><topic>Platelet-Derived Growth Factor - pharmacology</topic><topic>Protein-Serine-Threonine Kinases</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>RNA, Messenger - genetics</topic><topic>Signal Transduction</topic><topic>Transforming Growth Factor beta - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Reif, Shimon</creatorcontrib><creatorcontrib>Lang, Alon</creatorcontrib><creatorcontrib>Lindquist, Jeffery N</creatorcontrib><creatorcontrib>Yata, Yutaka</creatorcontrib><creatorcontrib>Gabele, Erwin</creatorcontrib><creatorcontrib>Scanga, Andrew</creatorcontrib><creatorcontrib>Brenner, David A</creatorcontrib><creatorcontrib>Rippe, Richard A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Reif, Shimon</au><au>Lang, Alon</au><au>Lindquist, Jeffery N</au><au>Yata, Yutaka</au><au>Gabele, Erwin</au><au>Scanga, Andrew</au><au>Brenner, David A</au><au>Rippe, Richard A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Role of Focal Adhesion Kinase-Phosphatidylinositol 3-Kinase-Akt Signaling in Hepatic Stellate Cell Proliferation and Type I Collagen Expression</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2003-03-07</date><risdate>2003</risdate><volume>278</volume><issue>10</issue><spage>8083</spage><epage>8090</epage><pages>8083-8090</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Following a fibrogenic stimulus, the hepatic stellate cell (HSC) undergoes a complex activation process associated with increased
cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase
(PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several cell types. We investigated
the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, cell attachment,
and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor
of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative
forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation,
did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative
effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and
inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, cell attachment, and PDGF-induced
cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K,
and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>12502711</pmid><doi>10.1074/jbc.M212927200</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Cell Adhesion Cell Division Cell Movement Cells, Cultured Chromones - pharmacology Collagen Type I - genetics Collagen Type I - metabolism Enzyme Inhibitors - pharmacology Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases Gene Expression Regulation - drug effects Liver - cytology Liver - drug effects Liver - enzymology Liver - metabolism Morpholines - pharmacology Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide-3 Kinase Inhibitors Phosphorylation Platelet-Derived Growth Factor - pharmacology Protein-Serine-Threonine Kinases Protein-Tyrosine Kinases - metabolism Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt Rats Rats, Sprague-Dawley RNA, Messenger - genetics Signal Transduction Transforming Growth Factor beta - physiology |
| title | The Role of Focal Adhesion Kinase-Phosphatidylinositol 3-Kinase-Akt Signaling in Hepatic Stellate Cell Proliferation and Type I Collagen Expression |
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