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• W828816376 abstract "The multifunctional guanine nucleotide exchange factor (GEF) Pebble (Pbl) is an essential player during cytokinesis and fibroblast growth factor-triggered mesoderm migration in the Drosophila gastrula. During cytokinesis, Pbl activates Rho1 at the cell cortex leading to the formation of the contractile actomyosin ring. Although Pbl’s role in the conserved cytokinesis pathway is well characterized, its migration-specific function is less well understood. The subcellular localization of Pbl as well as its GTPase substrate during mesoderm spreading is unknown. Furthermore, it is unclear how the switch between the dual functions of the GEF is mediated in order to guarantee a specific activation of the respective downstream pathways during cytokinesis and migration. To address these questions a domain-function analysis of the Pbl protein was conducted. This work showed that full-length Pbl localizes not only to the nucleus but also to the cell cortex and cellular protrusions in migrating cells. The PH domain and the conserved C-terminal tail are both involved in the cortical localization of Pbl. Several lines of evidence indicated that the Rac GTPase pathway is involved in mesoderm migration and that Rac is directly activated by Pbl. First, Rac genetically interacted with activated forms of Pbl in the compound eye of the fly. Lowering the dose of Rac weakened the dominant phenotype while co-expression of extra Rac led to an enhancement. Second, co-expression of wild type Rac1 enhanced the migration rescue of a constitutively active Pbl variant in a pbl loss-of-function background. Third, dominant Rac constructs were able to enhance migration defects in the hypomorphic pbl11D allele. Forth, expression of constitutive active Rac1 in the mesoderm lead, analogous to the misexpression of the constitutive active PblDH-PH, to an interference with proper mesoderm spreading. Fifth, loss of Rac1/Rac2 activity in the early embryo caused severe migration defects indicating the requirement for Rac GTPases in this process. Finally, biochemical data from a previous in vitro guanine-nucleotide-exchange-assay as well as in vitro GEF binding assays indicated that Rho1, Rac1 and Rac2 can all bind to the catalytic core of Pbl and that they are accepted as substrates. Results of gain-of-function and rescue experiments both suggested an important regulatory role for Pbl’s C-terminal tail for the selective activation of Rho1 vs. Rac dependent pathways. These data support a model in which post-translational modifications of Pbl, most likely at its conserved C-terminus, result in a change in its substrate preference. This enables at least a subpopulation of the GEF to trigger activation of Rac GTPases at the cell cortex thereby fulfilling its migration specific function." @default.
• W828816376 created "2016-06-24" @default.
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• W828816376 date "2009-01-01" @default.
• W828816376 modified "2023-09-23" @default.
• W828816376 title "Functional dissection of the Rho guanine nucleotide exchange factor Pebble in Drosophila mesoderm morphogenesis" @default.
• W828816376 hasPublicationYear "2009" @default.
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