Sci. Signal., 21 December 2010
Chemotaxis Migrating Cells Need TORC
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
Upon exposure to a chemoattractant, cells polarize to form a myosin II–dependent back (uropod) and an F-actin–rich front (pseudopod), which points in the direction of the gradient (see commentary by Charest and Firtel). Liu et al. studied the role of the mammalian target of rapamycin complex 2 (mTORC2), which is implicated in the responses of Dictyostelium to chemoattractants and in actin polymerization in neutrophils. In contrast to neutrophil-like cells expressing nonspecific small hairpin RNA (shRNA), cells expressing shRNA against the mTORC2 component Rictor (Rictor shRNA cells) did not polarize or migrate in the presence of the chemoattractant fMLP, although they could form F-actin. Migration of wild-type (WT) cells to fMLP was independent of Akt but was blocked by inhibition of protein kinase C (PKC), which did not prevent cell polarization but inhibited uropod retraction. Knockdown of Rictor also inhibited fMLP-induced generation of intracellular cyclic AMP (cAMP); cAMP generation in WT cells was dependent on PKC but not Akt. fMLP-induced cAMP production was defective in cells in which adenylyl cyclase 9 (AC9) was knocked down, and migration of AC9-defective cells was less efficient than that of WT cells and similar in extent to that of Rictor shRNA cells. This phenotype was also associated with a defect in retraction of the uropod. Imaging of migrating cells showed that cAMP was excluded from the pseudopods and stayed within the cell body; concentrations of cAMP varied dynamically at the rear of the cell. Knockdown of AC9 resulted in enhanced activity of RhoA and its downstream kinase ROCK, which phosphorylated myosin light chain, increased the activity of myosin II, and enhanced the persistence of the uropod. Indeed, assemblies of myosin II extended forward from the rear of the cell when AC9 was absent. Together, these data suggest that, in addition to regulating F-actin formation at the front of the cell, mTORC2 mediates the chemoattractant-induced generation of cAMP, which moves to the rear of the cell to regulate RhoA and myosin II.
L. Liu, S. Das, W. Losert, C. A. Parent, mTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion. Dev. Cell 19, 845–857 (2010). [PubMed]
P. G. Charest, R. A. Firtel, "TORCing" neutrophil chemotaxis. Dev. Cell 19, 795–796 (2010). [PubMed]
Citation: J. F. Foley, Migrating Cells Need TORC. Sci. Signal. 3, ec387 (2010).
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