title: Rab-geranylgeranyl transferase regulates glucose-stimulated insulin secretion from pancreatic β cells.
abstract: A growing body of evidence implicates essential roles for small molecular weight G-proteins (e.g., Cdc42, Rac1, Arf6 and Rab3A and Rab27A) in islet β-cell function including glucose-stimulated insulin secretion (GSIS). One of the known mechanisms for optimal activation of small G-proteins involves post-translational prenylation, which is mediated by farnesyltransferase (FTase) and geranylgeranyl transferases (GGTases I and II). The FTase catalyzes incorporation of a 15-carbon farnesyl group while the GGTase mediates incorporation of a 20-carbon geranylgeranyl group into the C-terminal cysteines of G-proteins. The FTase, GGTase I and GGTase II prenylate Ras, Cdc42/Rac1, and Rab G-proteins, respectively. While considerable evidence exists on FTase/GGTase I-mediated regulation of GSIS, very little is known about GGTase II (also referred to as Rab GGTase; RGGT) and its regulatory proteins in the cascade of events leading to GSIS. Herein, we provide the first immunological evidence to suggest expression of α- and β-subunits of RGGT in clonal INS 832/13 β-cells, normal rat islets and human islets. Furthermore, Rab escort protein1 (REP1), which has been shown to be critical for prenylation of Rab G-proteins, is also expressed in these cells. Furthermore, evidence is presented to suggest that siRNA-mediated knockdown of α- or β-subunits of RGGT and REP1 markedly attenuates GSIS in INS 832/13 cells. These findings provide the first evidence in support of key roles for RGGT and its regulatory proteins in GSIS.
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA.
authors.forename: Daleep K
authors.initials: DK
authors.lastname: Arora
authors.forename: Ismail
authors.initials: I
authors.lastname: Syed
authors.forename: Baker
authors.initials: B
authors.lastname: Machhadieh
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Kowluru
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000502:physiology; D019883:Alkyl and Aryl Transferases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513166:Chm protein, rat; D007328:Insulin; D034741:RNA, Small Interfering; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase; D005947:Glucose