The RhoGEF Pebble is required for cell shape changes during cell migration triggered by theDrosophilaFGF receptor Heartless

Abstract

The FGF receptor Heartless (HTL) is required for mesodermal cell migration in the Drosophila gastrula. We show that mesoderm cells undergo different phases of specific cell shape changes during mesoderm migration. During the migratory phase, the cells adhere to the basal surface of the ectoderm and exhibit extensive protrusive activity. HTL is required for the protrusive activity of the mesoderm cells. Moreover, the early phenotype of htl mutants suggests that HTL is required for the adhesion of mesoderm cells to the ectoderm.In a genetic screen we identified pebble (pbl) as a novel gene required for mesoderm migration. pbl encodes a guanyl nucleotide exchange factor (GEF) for RHO1 and is known as an essential regulator of cytokinesis. We show that the function of PBL in cell migration is independent of the function of PBL in cytokinesis. Although RHO1 acts as a substrate for PBL in cytokinesis, compromising RHO1 function in the mesoderm does not block cell migration. These data suggest that the function of PBL in cell migration might be mediated through a pathway distinct from RHO1. This idea is supported by allele-specific differences in the expressivity of the cytokinesis and cell migration phenotypes of different pbl mutants. We show that PBL is autonomously required in the mesoderm for cell migration. Like HTL, PBL is required for early cell shape changes during mesoderm migration. Expression of a constitutively active form of HTL is unable to rescue the early cellular defects in pbl mutants, suggesting that PBL is required for the ability of HTL to trigger these cell shape changes. These results provide evidence for a novel function of the Rho-GEF PBL in HTL-dependent mesodermal cell migration.

Genetic Evidence for Antagonism Between Pak Protein Kinase and Rho1 Small GTPase Signaling in Regulation of the Actin Cytoskeleton During Drosophila Oogenesis

“…There is evidence that RhoGEFs have functions distinct from small GTPase activation; for example, Pebble has a Rho1-independent role in mesoderm migration (Schumacher et al 2004;Rossman et al 2005).…”

The roles of CUX1 homeodomain proteins in the establishment of a transcriptional program required for cell migration and invasion

“…18 While Ect2 is known to play a role in mitosis, its ortholog Pebble has been shown to regulate cell migration and epithelial-mesenchymal transition, highlighting again the inter-relationship between these two cellular processes. 23,24 The importance of transcriptional regulation for Rho GTPases activity was confirmed both from siRNA-mediated knockdown of CUX1 as well as overexpression of p110 CUX1. Stable knockdown of CUX1 in two cell lines caused a reduction in the activity of RhoA, Cdc42 and Rac1.…”

EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line

“…Once FRS2a is phosphorylated, it recruits adaptor molecules such as Grb2 and Shp2 and relays the signals to the Ras/mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase/Akt pathway (22,23). In addition, FGFR is known to direct cytoskeletal reorganization through regulating small GTPases, although its precise signaling mechanism has not been clarified (24).…”