Cell Migration

Knowing the Front

Science's STKE  16 Aug 2005:
Vol. 2005, Issue 297, pp. tw296
DOI: 10.1126/stke.2972005tw296

Cells use different types of receptors to respond to extracellular cues that stimulate cell movement. Jékely et al. report that Drosophila border cells of the egg chamber, which rely on receptor tyrosine kinases (RTKs) for directed motility, use endocytosis of the receptors to control directionality of cell migration. In flies with a mutant form of the ubiquitin ligase Cbl or a mutant form of the guanine nucleotide exchange factor (GEF) Sprint (the homolog of mammalian RIN1), the border cells failed to migrate to the oocyte, which was exacerbated by overexpression of the RTKs [in this case, epidermal growth factor receptor (EGFR) and PVR, the Drosophila homolog of the platelet-derived growth factor and vascular endothelial growth factor]. The mutant cells also showed a loss of localized activity of the RTKs at the leading edge of the border cells. Cells mutant for Hrs, a protein required after internalization for degradation, or wild-type cells overexpressing the RTKs did not show migration defects despite having elevated, but still localized, RTK activity. Thus, it was not simply an excess activity of RTK that caused the migration defects in the Cbl- or Sprint-mutant cells. Yeast two-hybrid experiments showed that Cbl and Sprint both interacted with PVR in a phosphotyrosine-dependent manner. Expression of a PVR mutant that could not interact with Cbl and Sprint resulted in a low-penetrance migration defect and delocalized phosphotyrosine accumulation (a measure of RTK activity) in the border cells. Thus, for RTK-mediated migration of border cells, it appears that the absolute level of RTK activity is less critical than the location of that activity in the cell. Receptor endocytosis mediated by ubiquitin ligation is a critical step in restricting RTK activity, allowing the cells to move toward the ligand (see Le Roy and Wrana for commentary).

G. Jékely, H.-H. Sung, C. M. Luque, P. Rørth, Regulators of endocytosis maintain localized receptor tyrosine kinase signaling in guided migration. Dev. Cell 9, 197-207 (2005). [PubMed]

C. Le Roy, J. L. Wrana, Signaling and endocytosis: A team effort for cell migration. Dev. Cell 9, 167-168 (2005). [PubMed]