tailieunhanh - Báo cáo khoa học: Compartmentalized signalling: Ras proteins and signalling nanoclusters

Differential subcellular compartmentalization of the three main Ras isoforms (H-Ras, N-Ras and K-Ras) is believed to underlie their biological differences. Modulatable interactions between cellular membranes and Ras C-terminal hypervariable region motifs determine differences in trafficking and the relative proportions of each isoform in cell-surface signalling nanoclusters and intracellular endoplasmic reticulum⁄Golgi, endosomal and mitochondrial compartments. | ỊFEBS Journal MINIREVIEW Compartmentalized signalling Ras proteins and signalling nanoclusters Jasminka Omerovic and Ian A. Prior PhysiologicalLaboratory University of Liverpool UK Keywords compartmentalization GTPase isoforms MAP kinase microdomains nanoclusters Raf Ras receptor scaffold Correspondence I. A. Prior PhysiologicalLaboratory School of BiomedicalSciences University of Liverpool Crown St LiverpoolL69 3BX UK Fax 44 151 794 4434 Tel 44 151 794 5332 E-mail iprior@ Received 1 September 2008 revised 16 October 2008 accepted 24 November 2008 doi Differential subcellular compartmentalization of the three main Ras isoforms H-Ras N-Ras and K-Ras is believed to underlie their biological differences. Modulatable interactions between cellular membranes and Ras C-terminal hypervariable region motifs determine differences in trafficking and the relative proportions of each isoform in cell-surface signalling nanoclusters and intracellular endoplasmic reticulum Golgi endosomal and mitochondrial compartments. Ras regulators effectors and scaffolds are also differentially distributed potentially enabling preferential coupling to specific signalling pathways in each subcellular location. Here we summarize the mechanisms underlying compartment-specific Ras signalling and the outputs generated. Ras proteins are small GTPases that operate as molecular switches controlling the relay of signals from cell-surface receptors to a diverse array of intracellular effector cascades responsible for regulating cell proliferation differentiation and apoptosis 1 . Hyperactivating mutations of Ras promote cell transformation and contribute to oncogenesis in 15 of human cancer patients data obtained from the Wellcome Trust Sanger Institute Cancer Genome Project http www. genetics CGP . Although clearly important from a human health perspective Ras has also recently emerged as a key model system for investigating how the outputs .