Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis |
| |
| Authors: | Detter J C Zhang Q Mules E H Novak E K Mishra V S Li W McMurtrie E B Tchernev V T Wallace M R Seabra M C Swank R T Kingsmore S F |
| |
| Affiliation: | Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA. |
| |
| Abstract: | ![]()
Few molecular events important to platelet biogenesis have been identified. Mice homozygous for the spontaneous, recessive mutation gunmetal (gm) have prolonged bleeding, thrombocytopenia, and reduced platelet alpha- and delta-granule contents. Here we show by positional cloning that gm results from a G-->A substitution mutation in a splice acceptor site within the alpha-subunit of Rab geranylgeranyl transferase (Rabggta), an enzyme that attaches geranylgeranyl groups to Rab proteins. Most Rabggta mRNAs from gm tissues skipped exon 1 and lacked a start codon. Rabggta protein and Rab geranylgeranyl transferase (GGTase) activity were reduced 4-fold in gm platelets. Geranylgeranylation and membrane association of Rab27, a Rab GGTase substrate, were significantly decreased in gm platelets. These findings indicate that geranylgeranylation of Rab GTPases is critical for hemostasis. Rab GGTase inhibition may represent a new treatment for thrombocytosis and clotting disorders. |
| |
| Keywords: | |
| 本文献已被 PubMed 等数据库收录！ |
|
