Focal Adhesion Kinase Is Required for Intestinal Regeneration and Tumorigenesis Downstream of Wnt/c-Myc Signaling
The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration followin...
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| Veröffentlicht in: | Developmental cell 2010-08, Vol.19 (2), p.259-269 |
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| creator | Ashton, Gabrielle H. Morton, Jennifer P. Myant, Kevin Phesse, Toby J. Ridgway, Rachel A. Marsh, Victoria Wilkins, Julie A. Athineos, Dimitris Muncan, Vanesa Kemp, Richard Neufeld, Kristi Clevers, Hans Brunton, Valerie Winton, Douglas J. Wang, Xiaoyan Sears, Rosalie C. Clarke, Alan R. Frame, Margaret C. Sansom, Owen J. |
| description | The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer.
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► Wnt/Myc signaling promotes FAK expression in the intestine ► FAK contributes to Wnt/Myc-activated Akt/mTOR signaling ► FAK is essential for Wnt/Myc-activated intestinal regeneration and tumorigenesis |
| doi_str_mv | 10.1016/j.devcel.2010.07.015 |
| format | Article |
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► Wnt/Myc signaling promotes FAK expression in the intestine ► FAK contributes to Wnt/Myc-activated Akt/mTOR signaling ► FAK is essential for Wnt/Myc-activated intestinal regeneration and tumorigenesis</description><identifier>ISSN: 1534-5807</identifier><identifier>ISSN: 1878-1551</identifier><identifier>EISSN: 1878-1551</identifier><identifier>DOI: 10.1016/j.devcel.2010.07.015</identifier><identifier>PMID: 20708588</identifier><language>eng</language><publisher>Cambridge, MA: Elsevier Inc</publisher><subject>Animals ; Biological and medical sciences ; Cell differentiation, maturation, development, hematopoiesis ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; CELLCYCLE ; Focal Adhesion Protein-Tyrosine Kinases - genetics ; Focal Adhesion Protein-Tyrosine Kinases - metabolism ; Fundamental and applied biological sciences. Psychology ; Humans ; HUMDISEASE ; Intestinal Neoplasms - metabolism ; Intestinal Neoplasms - pathology ; Intestines - pathology ; Intestines - physiology ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Molecular and cellular biology ; Protein Serine-Threonine Kinases - genetics ; Protein Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Proto-Oncogene Proteins c-myc - genetics ; Proto-Oncogene Proteins c-myc - metabolism ; Regeneration ; Signal transduction ; Signal Transduction - physiology ; TOR Serine-Threonine Kinases ; Wnt Proteins - genetics ; Wnt Proteins - metabolism</subject><ispartof>Developmental cell, 2010-08, Vol.19 (2), p.259-269</ispartof><rights>2010 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>2010 Elsevier Inc. All rights reserved.</rights><rights>2010 Elsevier Inc. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c558t-66f73ba005d77e055b139fb47d918c158e4dbb70a221f924a53f1042ce3ec3c3</citedby><cites>FETCH-LOGICAL-c558t-66f73ba005d77e055b139fb47d918c158e4dbb70a221f924a53f1042ce3ec3c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1534580710003436$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27903,27904,65309</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23142764$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20708588$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ashton, Gabrielle H.</creatorcontrib><creatorcontrib>Morton, Jennifer P.</creatorcontrib><creatorcontrib>Myant, Kevin</creatorcontrib><creatorcontrib>Phesse, Toby J.</creatorcontrib><creatorcontrib>Ridgway, Rachel A.</creatorcontrib><creatorcontrib>Marsh, Victoria</creatorcontrib><creatorcontrib>Wilkins, Julie A.</creatorcontrib><creatorcontrib>Athineos, Dimitris</creatorcontrib><creatorcontrib>Muncan, Vanesa</creatorcontrib><creatorcontrib>Kemp, Richard</creatorcontrib><creatorcontrib>Neufeld, Kristi</creatorcontrib><creatorcontrib>Clevers, Hans</creatorcontrib><creatorcontrib>Brunton, Valerie</creatorcontrib><creatorcontrib>Winton, Douglas J.</creatorcontrib><creatorcontrib>Wang, Xiaoyan</creatorcontrib><creatorcontrib>Sears, Rosalie C.</creatorcontrib><creatorcontrib>Clarke, Alan R.</creatorcontrib><creatorcontrib>Frame, Margaret C.</creatorcontrib><creatorcontrib>Sansom, Owen J.</creatorcontrib><title>Focal Adhesion Kinase Is Required for Intestinal Regeneration and Tumorigenesis Downstream of Wnt/c-Myc Signaling</title><title>Developmental cell</title><addtitle>Dev Cell</addtitle><description>The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer.
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► Wnt/Myc signaling promotes FAK expression in the intestine ► FAK contributes to Wnt/Myc-activated Akt/mTOR signaling ► FAK is essential for Wnt/Myc-activated intestinal regeneration and tumorigenesis</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell differentiation, maturation, development, hematopoiesis</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>CELLCYCLE</subject><subject>Focal Adhesion Protein-Tyrosine Kinases - genetics</subject><subject>Focal Adhesion Protein-Tyrosine Kinases - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>HUMDISEASE</subject><subject>Intestinal Neoplasms - metabolism</subject><subject>Intestinal Neoplasms - pathology</subject><subject>Intestines - pathology</subject><subject>Intestines - physiology</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular and cellular biology</subject><subject>Protein Serine-Threonine Kinases - genetics</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Regeneration</subject><subject>Signal transduction</subject><subject>Signal Transduction - physiology</subject><subject>TOR Serine-Threonine Kinases</subject><subject>Wnt Proteins - genetics</subject><subject>Wnt Proteins - metabolism</subject><issn>1534-5807</issn><issn>1878-1551</issn><issn>1878-1551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctuEzEUhi0EojfeACFvEKtJ7fE49myQqtJCRBESjcTS8tjHqaMZu7FnUvXt6yihhQ0rW-f8_7l9CL2nZEYJnZ-vZxa2BvpZTUqIiBmh_BU6plLIinJOX5c_Z03FJRFH6CTnNSk2KslbdFQTQSSX8hhtrqPRPb6wd5B9DPi7DzoDXmT8CzaTT2Cxiwkvwgh5LLm-xFcQIOlxJ9fB4uU0xOR3wewz_hIfQh4T6AFHh3-H8dxUPx4NvvWr4vZhdYbeON1neHd4T9Hy-mp5-a26-fl1cXlxUxnO5VjN506wThPCrRBAOO8oa13XCNtSaSiX0NiuE0TXNXVt3WjOHCVNbYCBYYados_7svdTN4A1EMake3Wf_KDTo4raq38zwd-pVdwqVrdUUFEKfDoUSHEzle3V4HO5d68DxCkr0chWsJbwomz2SpNizgnccxdK1I6VWqs9K7VjpYhQhVWxffh7wmfTHzhF8PEg0LlAckkH4_OLjtGmFvPmZVUo59x6SCobD8GALfzMqGz0_5_kCfF9tkU</recordid><startdate>20100817</startdate><enddate>20100817</enddate><creator>Ashton, Gabrielle H.</creator><creator>Morton, Jennifer P.</creator><creator>Myant, Kevin</creator><creator>Phesse, Toby J.</creator><creator>Ridgway, Rachel A.</creator><creator>Marsh, Victoria</creator><creator>Wilkins, Julie A.</creator><creator>Athineos, Dimitris</creator><creator>Muncan, Vanesa</creator><creator>Kemp, Richard</creator><creator>Neufeld, Kristi</creator><creator>Clevers, Hans</creator><creator>Brunton, Valerie</creator><creator>Winton, Douglas J.</creator><creator>Wang, Xiaoyan</creator><creator>Sears, Rosalie C.</creator><creator>Clarke, Alan R.</creator><creator>Frame, Margaret C.</creator><creator>Sansom, Owen J.</creator><general>Elsevier Inc</general><general>Cell Press</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</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><scope>5PM</scope></search><sort><creationdate>20100817</creationdate><title>Focal Adhesion Kinase Is Required for Intestinal Regeneration and Tumorigenesis Downstream of Wnt/c-Myc Signaling</title><author>Ashton, Gabrielle H. ; Morton, Jennifer P. ; Myant, Kevin ; Phesse, Toby J. ; Ridgway, Rachel A. ; Marsh, Victoria ; Wilkins, Julie A. ; Athineos, Dimitris ; Muncan, Vanesa ; Kemp, Richard ; Neufeld, Kristi ; Clevers, Hans ; Brunton, Valerie ; Winton, Douglas J. ; Wang, Xiaoyan ; Sears, Rosalie C. ; Clarke, Alan R. ; Frame, Margaret C. ; Sansom, Owen J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c558t-66f73ba005d77e055b139fb47d918c158e4dbb70a221f924a53f1042ce3ec3c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cell differentiation, maturation, development, hematopoiesis</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>CELLCYCLE</topic><topic>Focal Adhesion Protein-Tyrosine Kinases - genetics</topic><topic>Focal Adhesion Protein-Tyrosine Kinases - metabolism</topic><topic>Fundamental and applied biological sciences. 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Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer.
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► Wnt/Myc signaling promotes FAK expression in the intestine ► FAK contributes to Wnt/Myc-activated Akt/mTOR signaling ► FAK is essential for Wnt/Myc-activated intestinal regeneration and tumorigenesis</abstract><cop>Cambridge, MA</cop><pub>Elsevier Inc</pub><pmid>20708588</pmid><doi>10.1016/j.devcel.2010.07.015</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Developmental cell, 2010-08, Vol.19 (2), p.259-269 |
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| subjects | Animals Biological and medical sciences Cell differentiation, maturation, development, hematopoiesis Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes CELLCYCLE Focal Adhesion Protein-Tyrosine Kinases - genetics Focal Adhesion Protein-Tyrosine Kinases - metabolism Fundamental and applied biological sciences. Psychology Humans HUMDISEASE Intestinal Neoplasms - metabolism Intestinal Neoplasms - pathology Intestines - pathology Intestines - physiology Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Male Mice Mice, Inbred C57BL Molecular and cellular biology Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Regeneration Signal transduction Signal Transduction - physiology TOR Serine-Threonine Kinases Wnt Proteins - genetics Wnt Proteins - metabolism |
| title | Focal Adhesion Kinase Is Required for Intestinal Regeneration and Tumorigenesis Downstream of Wnt/c-Myc Signaling |
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