{"id":{"repo_id":"utmb","oai_identifier":"oai:utmb-ir.tdl.org:2152.3/160"},"canonical_url":"https://search.dev.ndltd.org/etd/utmb/oai:utmb-ir.tdl.org:2152.3/160","repository":{"repo_id":"utmb","name":"University of Texas Medical Branch","base_url":"https://utmb-ir.tdl.org/server/oai/request"},"display":{"title":"RAF-1 kinase inhibitor protein-mediated cholecystokinin-2 receptor desensitization and extracellular signal-regulated kinase activation","abstract":"Raf-1 kinase inhibitor protein (RKIP) is initially known as a suppressor for Raf-1-mediated ERK activation. Moreover, recent findings indicate that RKIP also has a role in G-protein-coupled receptor (GPCR) desensitization. Protein kinase C (PKC)-mediated phosphorylation at Serine 153 (S153) on RKIP switches RKIP association from Raf-1 to GPCR kinase-2 (GRK2) for inhibiting GRK2-mediated G-protein-coupled receptor (GPCR) desensitization. As a member of the GPCR superfamily, Cholecystokinin-2 receptor (CCK2R) is a physiological receptor for gastrin (G17) and activates extracellular signal-regulated kinase (ERK) via the PKC activity. The inhibition of classical PKCs (cPKC, PKC-α,-β, and -γ) by Gö6976 indicated the augment in ERK activation compared to vehicle control, suggesting cPKC’s involvement in CCK2R desensitization. CCK2R-mediated ERK activation was significantly decreased when PKC-δ was selectively silenced by siRNAs, indicating that PKC-δ, a member of the novel PKC family, mediates CCK2R-induced ERK activation. Furthermore, the data for CCK2R desensitization showed that inhibited cPKC activity by Gö6976 facilitated CCK2R desensitization. However, the silencing for PKC-α,-β, or –δ by siRNAs indicated that each knockdown of PKC isozymes attenuated CCK2R desensitization. The PKC involvement in CCK2R desensitization and ERK activation also suggested a potential role of RKIP in regulation of CCK2R activity. By either silencing or overexpressing RKIPs, I proved that RKIP acts as a suppressor for CCK2R desensitization, and the phosphorylation at S153 on RKIP plays a crucial role for inhibiting desensitization. The RKIP-mediated inhibition of CCK2R desensitization also resulted in augmentation of receptor-induced ERK activation, and this finding indicates that RKIP acts as a modulator for CCK2R-mediated signaling. The mechanism for RKIP-mediated receptor desensitization was investigated by co-immunoprecipitation of GRK2 with RKIP. The data indicated that RKIP strongly associated onto GRK2 when PKC was activated by phorbol 12-myristate 13-acetate (PMA) treatment, but either G17 stimulation or Gö6976 did not affect on the association. It suggests that PMA-sensitive PKC isozymes are responsible for RKIP phosphorylation; however, CCK2R-mediated PKC isozymes are not involved in RKIP phosphorylation directly, rather PKC activation by other cellular mechanisms mediate RKIP phosphorylation resulting in GRK2 association. Therefore, I conclude that RKIP mediates CCK2R desensitization and ERK activation through PKC activation.","abstract_html":"Raf-1 kinase inhibitor protein (RKIP) is initially known as a suppressor for Raf-1-mediated ERK activation. Moreover, recent findings indicate that RKIP also has a role in G-protein-coupled receptor (GPCR) desensitization. Protein kinase C (PKC)-mediated phosphorylation at Serine 153 (S153) on RKIP switches RKIP association from Raf-1 to GPCR kinase-2 (GRK2) for inhibiting GRK2-mediated G-protein-coupled receptor (GPCR) desensitization. As a member of the GPCR superfamily, Cholecystokinin-2 receptor (CCK2R) is a physiological receptor for gastrin (G17) and activates extracellular signal-regulated kinase (ERK) via the PKC activity. The inhibition of classical PKCs (cPKC, PKC-α,-β, and -γ) by Gö6976 indicated the augment in ERK activation compared to vehicle control, suggesting cPKC’s involvement in CCK2R desensitization. CCK2R-mediated ERK activation was significantly decreased when PKC-δ was selectively silenced by siRNAs, indicating that PKC-δ, a member of the novel PKC family, mediates CCK2R-induced ERK activation. Furthermore, the data for CCK2R desensitization showed that inhibited cPKC activity by Gö6976 facilitated CCK2R desensitization. However, the silencing for PKC-α,-β, or –δ by siRNAs indicated that each knockdown of PKC isozymes attenuated CCK2R desensitization. The PKC involvement in CCK2R desensitization and ERK activation also suggested a potential role of RKIP in regulation of CCK2R activity. By either silencing or overexpressing RKIPs, I proved that RKIP acts as a suppressor for CCK2R desensitization, and the phosphorylation at S153 on RKIP plays a crucial role for inhibiting desensitization. The RKIP-mediated inhibition of CCK2R desensitization also resulted in augmentation of receptor-induced ERK activation, and this finding indicates that RKIP acts as a modulator for CCK2R-mediated signaling. The mechanism for RKIP-mediated receptor desensitization was investigated by co-immunoprecipitation of GRK2 with RKIP. The data indicated that RKIP strongly associated onto GRK2 when PKC was activated by phorbol 12-myristate 13-acetate (PMA) treatment, but either G17 stimulation or Gö6976 did not affect on the association. It suggests that PMA-sensitive PKC isozymes are responsible for RKIP phosphorylation; however, CCK2R-mediated PKC isozymes are not involved in RKIP phosphorylation directly, rather PKC activation by other cellular mechanisms mediate RKIP phosphorylation resulting in GRK2 association. Therefore, I conclude that RKIP mediates CCK2R desensitization and ERK activation through PKC activation.","abstract_has_math":false,"creators":["Jeseong Park"],"institution":"The University of Texas Medical Branch","degree_name":"PhD","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Lisa A. Elferink"],"committee_chairs":[],"committee_members":["Robert A. Davey","Mark R. Hellmich","Glenn S. Kroog","Celia Chao"],"year":2009,"date_issued":"2009-06-29","date_published":"2009-06-29","updated_at":"2026-07-24T05:51:10Z","subjects":["RKIP","PKC","GRK2","GPCR desensitization","CCK2R"],"languages":["eng"],"rights":["Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works."],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["etd-07152009-103854"],"render_values":[{"text":"etd-07152009-103854","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2152.3/160","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Lisa A. Elferink"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Robert A. Davey","Mark R. Hellmich","Glenn S. Kroog","Celia Chao"]},{"key":"dc:creator","label":"Author","values":["Jeseong Park"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2011-12-20T16:04:56Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2010-09-28","2011-12-20T16:04:56Z"]},{"key":"dc:date.issued","label":"Date","values":["2009-06-29"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["PhD"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["The University of Texas Medical Branch"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["RKIP","PKC","GRK2","GPCR desensitization","CCK2R"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["etd-07152009-103854"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/2152.3/160"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Raf-1 kinase inhibitor protein (RKIP) is initially known as a suppressor for Raf-1-mediated ERK activation. Moreover, recent findings indicate that RKIP also has a role in G-protein-coupled receptor (GPCR) desensitization. Protein kinase C (PKC)-mediated phosphorylation at Serine 153 (S153) on RKIP switches RKIP association from Raf-1 to GPCR kinase-2 (GRK2) for inhibiting GRK2-mediated G-protein-coupled receptor (GPCR) desensitization. As a member of the GPCR superfamily, Cholecystokinin-2 receptor (CCK2R) is a physiological receptor for gastrin (G17) and activates extracellular signal-regulated kinase (ERK) via the PKC activity. The inhibition of classical PKCs (cPKC, PKC-α,-β, and -γ) by Gö6976 indicated the augment in ERK activation compared to vehicle control, suggesting cPKC’s involvement in CCK2R desensitization. CCK2R-mediated ERK activation was significantly decreased when PKC-δ was selectively silenced by siRNAs, indicating that PKC-δ, a member of the novel PKC family, mediates CCK2R-induced ERK activation. Furthermore, the data for CCK2R desensitization showed that inhibited cPKC activity by Gö6976 facilitated CCK2R desensitization. However, the silencing for PKC-α,-β, or –δ by siRNAs indicated that each knockdown of PKC isozymes attenuated CCK2R desensitization. The PKC involvement in CCK2R desensitization and ERK activation also suggested a potential role of RKIP in regulation of CCK2R activity. By either silencing or overexpressing RKIPs, I proved that RKIP acts as a suppressor for CCK2R desensitization, and the phosphorylation at S153 on RKIP plays a crucial role for inhibiting desensitization. The RKIP-mediated inhibition of CCK2R desensitization also resulted in augmentation of receptor-induced ERK activation, and this finding indicates that RKIP acts as a modulator for CCK2R-mediated signaling. The mechanism for RKIP-mediated receptor desensitization was investigated by co-immunoprecipitation of GRK2 with RKIP. The data indicated that RKIP strongly associated onto GRK2 when PKC was activated by phorbol 12-myristate 13-acetate (PMA) treatment, but either G17 stimulation or Gö6976 did not affect on the association. It suggests that PMA-sensitive PKC isozymes are responsible for RKIP phosphorylation; however, CCK2R-mediated PKC isozymes are not involved in RKIP phosphorylation directly, rather PKC activation by other cellular mechanisms mediate RKIP phosphorylation resulting in GRK2 association. Therefore, I conclude that RKIP mediates CCK2R desensitization and ERK activation through PKC activation."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["electronic"]},{"key":"dc:title","label":"Title","values":["RAF-1 kinase inhibitor protein-mediated cholecystokinin-2 receptor desensitization and extracellular signal-regulated kinase activation"]}]}],"canonical_facts":{"dc:contributor.advisor":["Lisa A. Elferink"],"dc:contributor.committeemember":["Robert A. Davey","Mark R. Hellmich","Glenn S. Kroog","Celia Chao"],"dc:creator":["Jeseong Park"],"dc:date.accessioned":["2011-12-20T16:04:56Z"],"dc:date.available":["2010-09-28","2011-12-20T16:04:56Z"],"dc:date.issued":["2009-06-29"],"dc:description.abstract":["Raf-1 kinase inhibitor protein (RKIP) is initially known as a suppressor for Raf-1-mediated ERK activation. Moreover, recent findings indicate that RKIP also has a role in G-protein-coupled receptor (GPCR) desensitization. Protein kinase C (PKC)-mediated phosphorylation at Serine 153 (S153) on RKIP switches RKIP association from Raf-1 to GPCR kinase-2 (GRK2) for inhibiting GRK2-mediated G-protein-coupled receptor (GPCR) desensitization. As a member of the GPCR superfamily, Cholecystokinin-2 receptor (CCK2R) is a physiological receptor for gastrin (G17) and activates extracellular signal-regulated kinase (ERK) via the PKC activity. The inhibition of classical PKCs (cPKC, PKC-α,-β, and -γ) by Gö6976 indicated the augment in ERK activation compared to vehicle control, suggesting cPKC’s involvement in CCK2R desensitization. CCK2R-mediated ERK activation was significantly decreased when PKC-δ was selectively silenced by siRNAs, indicating that PKC-δ, a member of the novel PKC family, mediates CCK2R-induced ERK activation. Furthermore, the data for CCK2R desensitization showed that inhibited cPKC activity by Gö6976 facilitated CCK2R desensitization. However, the silencing for PKC-α,-β, or –δ by siRNAs indicated that each knockdown of PKC isozymes attenuated CCK2R desensitization. The PKC involvement in CCK2R desensitization and ERK activation also suggested a potential role of RKIP in regulation of CCK2R activity. By either silencing or overexpressing RKIPs, I proved that RKIP acts as a suppressor for CCK2R desensitization, and the phosphorylation at S153 on RKIP plays a crucial role for inhibiting desensitization. The RKIP-mediated inhibition of CCK2R desensitization also resulted in augmentation of receptor-induced ERK activation, and this finding indicates that RKIP acts as a modulator for CCK2R-mediated signaling. The mechanism for RKIP-mediated receptor desensitization was investigated by co-immunoprecipitation of GRK2 with RKIP. The data indicated that RKIP strongly associated onto GRK2 when PKC was activated by phorbol 12-myristate 13-acetate (PMA) treatment, but either G17 stimulation or Gö6976 did not affect on the association. It suggests that PMA-sensitive PKC isozymes are responsible for RKIP phosphorylation; however, CCK2R-mediated PKC isozymes are not involved in RKIP phosphorylation directly, rather PKC activation by other cellular mechanisms mediate RKIP phosphorylation resulting in GRK2 association. Therefore, I conclude that RKIP mediates CCK2R desensitization and ERK activation through PKC activation."],"dc:format.medium":["electronic"],"dc:identifier.other":["etd-07152009-103854"],"dc:identifier.uri":["http://hdl.handle.net/2152.3/160"],"dc:language.iso":["eng"],"dc:rights":["Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works."],"dc:subject":["RKIP","PKC","GRK2","GPCR desensitization","CCK2R"],"dc:title":["RAF-1 kinase inhibitor protein-mediated cholecystokinin-2 receptor desensitization and extracellular signal-regulated kinase activation"],"thesis:degree_level":["Doctoral"],"thesis:degree_name":["PhD"],"thesis:institution_name":["The University of Texas Medical Branch"]},"updated_at":"2026-07-24T05:51:10Z"}