Putting Neutrophils in Motion

mTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion.

mTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion.

During chemotaxis, immune cells such as neutrophils orient themselves and move along a chemical gradient that is induced by chemicals called chemoattractants. Chemoattractants bind to specific G-protein linked receptors to put things in motion. The binding triggers the dissociation of the Gα-subunit from the Gβγ-subunit, which activate several downstream signaling cascades. This ultimately leads to the polarization of actin and myosin filament networks at the front and back of cells, respectively. The end result is directed cell migration, which is important in a wide range of physiological responses including wound healing and leukocyte trafficking, as well as in pathological processes such as metastasis.

The mammalian target of rapamycin (mTOR) is an atypical serine/threonine protein kinase that integrates signals from growth factors, nutrients, and stress detectors. mTOR is found in two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). In a recent paper published in Developmental Cell, Lunhua Liu, Ph.D., and his colleagues working under Carole Parent, Ph.D., in the Laboratory of Cellular and Molecular Biology, show that mTORC2 activity regulates neutrophil chemotaxis. Using a gene knock-down approach they show that interfering with mTORC2 leads to a loss of polarized actin assembly and myosin regulation, the networks needed for neutrophils to travel. Specifically, by knocking down a key component of mTORC2, Rictor, they show that chemoattractants can no longer induce the molecular signal needed to put neutrophils in motion. They discover that the critically necessary molecule is cAMP, which is synthesized by the adenylyl cyclase 9 (AC9).

mTORC2 puts neutrophils (pink) in motion.

mTORC2 puts neutrophils (pink) in motion.

Cells with altered AC9 levels exhibit specific and severe tail retraction defects that are mediated through RhoA. Furthermore, they establish that cAMP is excluded from extending pseudopods and remains restricted to the cell body of migrating neutrophils, where it is poised to regulate RhoA activity and back retraction. So the mTORC2-dependent regulation of myosin, an important component of the actin-myosin filament network, occurs through a cAMP/RhoA signaling axis, which is independent of actin’s reorganization during neutrophil chemotaxis. The molecule cAMP appears to be essential for chemoattractant-mediated processes, and it helps mTORC2 to properly regulate cytoskeletal elements during migration.

Summary Posted: 12/2010

Reference

Reviewed by Donna Kerrigan PubMed Link