Tyrosine-phosphorylated FAK is required for the hypertrophic response of cardiomyocytes to growth factors and mechanical load, but the role of FAK serine phosphorylation in this process is unknown. Endothelin-1 (ET-1; 1-100nM, 2-30min) and other hypertrophic factors induced a time- and dose-dependent increase in FAK-S910 phosphorylation in neonatal rat ventricular myocytes (NRVM). FAK-S910 phosphorylation required ETAR-dependent activation of PKCδ and Src via parallel Raf-1→MEK1/2→ERK1/2 and MEK5→ERK5 signaling pathways. Using co-immunoprecipitation, TIRF-microscopy and FRAP, ET-1 stimulation of NRVM expressing a nonphosphorylatable, S910A-FAK mutant decreased the interaction of paxillin and vinculin within costameres. This interaction was important in stabilizing α-actinin within the protein complex, as evident by a decrease in kFRAP for α-actinin-YFP. The S910A-FAK mutant also blocked ET-1 induced NRVM spreading and cyotoskeletal reorganization. Finally, we found that FAK was serine-phosphorylated at multiple sites in nonfailing, human LV tissue. FAK-S910 phosphorylation and ERK5 expression were dramatically reduced in patients undergoing heart transplantation for end-stage DCM. FAK undergoes S910 phosphorylation via PKCδ and Src-dependent pathways that are important for cell spreading and sarcomere reorganization. Reduced FAK-S910 phosphorylation may contribute to sarcomere disorganization in DCM.
","abstract_html":"<p>Tyrosine-phosphorylated FAK is required for the hypertrophic response of cardiomyocytes to growth factors and mechanical load, but the role of FAK serine phosphorylation in this process is unknown. Endothelin-1 (ET-1; 1-100nM, 2-30min) and other hypertrophic factors induced a time- and dose-dependent increase in FAK-S910 phosphorylation in neonatal rat ventricular myocytes (NRVM). FAK-S910 phosphorylation required ET<sub>A</sub>R-dependent activation of PKCδ and Src via parallel Raf-1→MEK1/2→ERK1/2 and MEK5→ERK5 signaling pathways. Using co-immunoprecipitation, TIRF-microscopy and FRAP, ET-1 stimulation of NRVM expressing a nonphosphorylatable, S910A-FAK mutant decreased the interaction of paxillin and vinculin within costameres. This interaction was important in stabilizing α-actinin within the protein complex, as evident by a decrease in <sub>k</sub>FRAP for α-actinin-YFP. The S910A-FAK mutant also blocked ET-1 induced NRVM spreading and cyotoskeletal reorganization. Finally, we found that FAK was serine-phosphorylated at multiple sites in nonfailing, human LV tissue. FAK-S910 phosphorylation and ERK5 expression were dramatically reduced in patients undergoing heart transplantation for end-stage DCM. FAK undergoes S910 phosphorylation via PKCδ and Src-dependent pathways that are important for cell spreading and sarcomere reorganization. Reduced FAK-S910 phosphorylation may contribute to sarcomere disorganization in DCM.</p>","abstract_has_math":false,"creators":["Chu, Miensheng"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Physiology","degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2012,"date_issued":"2012-01-01T08:00:00Z","date_published":"2012-01-01T08:00:00Z","updated_at":"2026-07-24T02:55:23Z","subjects":["costamere","dilated cardiomyopathy","FAK","Protein Kinase C","signal transduction","Src","Cellular and Molecular Physiology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://ecommons.luc.edu/luc_diss/298","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Chu, Miensheng"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2016-03-31T17:09:59Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Physiology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["costamere","dilated cardiomyopathy","FAK","Protein Kinase C","signal transduction","Src","Cellular and Molecular Physiology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://ecommons.luc.edu/luc_diss/298"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Tyrosine-phosphorylated FAK is required for the hypertrophic response of cardiomyocytes to growth factors and mechanical load, but the role of FAK serine phosphorylation in this process is unknown. Endothelin-1 (ET-1; 1-100nM, 2-30min) and other hypertrophic factors induced a time- and dose-dependent increase in FAK-S910 phosphorylation in neonatal rat ventricular myocytes (NRVM). FAK-S910 phosphorylation required ETAR-dependent activation of PKCδ and Src via parallel Raf-1→MEK1/2→ERK1/2 and MEK5→ERK5 signaling pathways. Using co-immunoprecipitation, TIRF-microscopy and FRAP, ET-1 stimulation of NRVM expressing a nonphosphorylatable, S910A-FAK mutant decreased the interaction of paxillin and vinculin within costameres. This interaction was important in stabilizing α-actinin within the protein complex, as evident by a decrease in kFRAP for α-actinin-YFP. The S910A-FAK mutant also blocked ET-1 induced NRVM spreading and cyotoskeletal reorganization. Finally, we found that FAK was serine-phosphorylated at multiple sites in nonfailing, human LV tissue. FAK-S910 phosphorylation and ERK5 expression were dramatically reduced in patients undergoing heart transplantation for end-stage DCM. FAK undergoes S910 phosphorylation via PKCδ and Src-dependent pathways that are important for cell spreading and sarcomere reorganization. Reduced FAK-S910 phosphorylation may contribute to sarcomere disorganization in DCM.
"]},{"key":"dc:title","label":"Title","values":["Serine 910 Phosphorylation of Focal Adhesion Kinase Is Critical for Costamere Assembly"]}]}],"canonical_facts":{"dc:creator":["Chu, Miensheng"],"dc:date.available":["2016-03-31T17:09:59Z"],"dc:description.abstract":["Tyrosine-phosphorylated FAK is required for the hypertrophic response of cardiomyocytes to growth factors and mechanical load, but the role of FAK serine phosphorylation in this process is unknown. Endothelin-1 (ET-1; 1-100nM, 2-30min) and other hypertrophic factors induced a time- and dose-dependent increase in FAK-S910 phosphorylation in neonatal rat ventricular myocytes (NRVM). FAK-S910 phosphorylation required ETAR-dependent activation of PKCδ and Src via parallel Raf-1→MEK1/2→ERK1/2 and MEK5→ERK5 signaling pathways. Using co-immunoprecipitation, TIRF-microscopy and FRAP, ET-1 stimulation of NRVM expressing a nonphosphorylatable, S910A-FAK mutant decreased the interaction of paxillin and vinculin within costameres. This interaction was important in stabilizing α-actinin within the protein complex, as evident by a decrease in kFRAP for α-actinin-YFP. The S910A-FAK mutant also blocked ET-1 induced NRVM spreading and cyotoskeletal reorganization. Finally, we found that FAK was serine-phosphorylated at multiple sites in nonfailing, human LV tissue. FAK-S910 phosphorylation and ERK5 expression were dramatically reduced in patients undergoing heart transplantation for end-stage DCM. FAK undergoes S910 phosphorylation via PKCδ and Src-dependent pathways that are important for cell spreading and sarcomere reorganization. Reduced FAK-S910 phosphorylation may contribute to sarcomere disorganization in DCM.
"],"dc:identifier":["https://ecommons.luc.edu/luc_diss/298"],"dc:subject":["costamere","dilated cardiomyopathy","FAK","Protein Kinase C","signal transduction","Src","Cellular and Molecular Physiology"],"dc:title":["Serine 910 Phosphorylation of Focal Adhesion Kinase Is Critical for Costamere Assembly"],"thesis:degree_discipline":["Physiology"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T02:55:23Z"}