title: Cell-specific abnormal prenylation of Rab proteins in platelets and melanocytes of the gunmetal mouse.
abstract: The mutant gunmetal mouse exhibits reduced rates of platelet synthesis, abnormalities of platelet alpha and dense granules and hypopigmentation. Several of these features resemble those of human alpha/delta platelet storage pool disease, grey platelet syndrome and Hermansky-Pudlak syndrome. Gunmetal mice have reduced levels of Rab geranylgeranyltransferase (RabGGTase), which adds lipophilic prenyl groups to the carboxyl terminus of Rab proteins. The degree of prenylation and the subcellular distribution of several Rab proteins were evaluated in mutant platelets, melanocytes and other tissues. Significant deficits in prenylation and membrane binding of most Rabs were observed in platelets and melanocytes. In contrast, minimal alterations in Rab prenylation were apparent in several other gunmetal tissues despite the fact that RabGGTase activity was equally diminished in these tissues. The mutant tissue-specific effects are probably due to increased concentrations of Rab proteins in platelets and melanocytes. These experiments show that Rab proteins are differentially sensitive to levels of RabGGTase activity and that normal platelet synthesis, platelet organelle function and normal pigmentation are highly sensitive to the degree of prenylation and membrane association of Rab proteins. Further, the tissue-specific effects of the gunmetal mutation suggest that RabGGTase is a potential target for therapy of thrombocytosis.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhen
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Edward K
authors.initials: EK
authors.lastname: Novak
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Collinson
authors.forename: Elliott K
authors.initials: EK
authors.lastname: Jang
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Haslam
authors.forename: Rosemary W
authors.initials: RW
authors.lastname: Elliott
authors.forename: Richard T
authors.initials: RT
authors.lastname: Swank
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D008544:Melanocytes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D015388:Organelles / Q000378:metabolism; D010981:Platelet Storage Pool Deficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017368:Protein Prenylation; D020691:rab GTP-Binding Proteins / Q000235:genetics*
chemical_list: D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase; D020691:rab GTP-Binding Proteins