{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T03:39:18Z","timestamp":1791430758998,"version":"4.3.3"},"reference-count":49,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ras-related Rap1A GTPase is implicated in pancreas \u03b2-cell insulin secretion and is stimulated by the cAMP sensor Epac2, a guanine exchange factor and activator of Rap1 GTPase. In this study, we examined the differential proteomic profiles of pancreata from C57BL\/6 Rap1A-deficient (Null) and control wild-type (WT) mice with nanoLC-ESI-MS\/MS to assess targets of Rap1A potentially involved in insulin regulation. We identified 77 overlapping identifier proteins in both groups, with 8 distinct identifier proteins in Null versus 56 distinct identifier proteins in WT mice pancreata. Functional enrichment analysis showed four of the eight Null unique proteins, ERO1-like protein \u03b2 (Ero1l\u03b2), triosephosphate isomerase (TP1), 14-3-3 protein \u03b3, and kallikrein-1, were exclusively involved in insulin biogenesis, with roles in insulin metabolism. Specifically, the mRNA expression of Ero1l\u03b2 and TP1 was significantly (p &lt; 0.05) increased in Null versus WT pancreata. Rap1A deficiency significantly affected glucose tolerance during the first 15\u201330 min of glucose challenge but showed no impact on insulin sensitivity. Ex vivo glucose-stimulated insulin secretion (GSIS) studies on isolated Null islets showed significantly impaired GSIS. Furthermore, in GSIS-impaired islets, the cAMP-Epac2-Rap1A pathway was significantly compromised compared to the WT. Altogether, these studies underscore an essential role of Rap1A GTPase in pancreas physiological function.<\/jats:p>","DOI":"10.3390\/ijms25158013","type":"journal-article","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T14:26:50Z","timestamp":1721744810000},"page":"8013","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Proteomic Analysis of Rap1A GTPase Signaling-Deficient C57BL\/6 Mouse Pancreas and Functional Studies Identify an Essential Role of Rap1A in Pancreas Physiology"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4962-5078","authenticated-orcid":false,"given":"Durrey","family":"Shahwar","sequence":"first","affiliation":[{"name":"Molecular Signaling Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadaf","family":"Baqai","sequence":"additional","affiliation":[{"name":"Molecular Signaling Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faisal","family":"Khan","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"},{"name":"Husein Ebrahim Jamal (H.E.J.) Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1645-6139","authenticated-orcid":false,"given":"M. Israr","family":"Khan","sequence":"additional","affiliation":[{"name":"Molecular Diabetology Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shafaq","family":"Javaid","sequence":"additional","affiliation":[{"name":"Molecular Signaling Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5907-4325","authenticated-orcid":false,"given":"Abdul","family":"Hameed","sequence":"additional","affiliation":[{"name":"Ziauddin College of Molecular Medicine, Ziauddin University, Clifton, Karachi 75600, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aisha","family":"Raza","sequence":"additional","affiliation":[{"name":"Molecular Signaling Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadaf","family":"Saleem Uddin","sequence":"additional","affiliation":[{"name":"Molecular Signaling Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hina","family":"Hazrat","sequence":"additional","affiliation":[{"name":"Molecular Signaling Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Hafizur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Molecular Diabetology Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"},{"name":"Daffodil International University, Birulia, Savar, Dhaka 1216, Bangladesh"},{"name":"Dhaka International University, Satarkul, Badda, Dhaka 1212, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Ghulam","family":"Musharraf","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"},{"name":"Husein Ebrahim Jamal (H.E.J.) Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7111-828X","authenticated-orcid":false,"given":"Maqsood A.","family":"Chotani","sequence":"additional","affiliation":[{"name":"Molecular Signaling Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1242\/jcs.00238","article-title":"Cellular functions of the Rap1 GTP-binding protein: A pattern emerges","volume":"116","author":"Caron","year":"2003","journal-title":"J. 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