Actuation of single downstream nodes in growth factor network steers immune cell migration

• Published in: Developmental cell Vol. 58; no. 13; pp. 1170 - 1188.e7
• Main Authors: Pal, Dhiman Sankar, Banerjee, Tatsat, Lin, Yiyan, de Trogoff, Félix, Borleis, Jane, Iglesias, Pablo A., Devreotes, Peter N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.07.2023
• Subjects: actin cytoskeleton; Animals; biochemical excitability; cancer; Cell Movement - physiology; development; Dictyostelium - metabolism; Humans; immunity; immunotherapy; Intercellular Signaling Peptides and Proteins; leukocytes; Mechanistic Target of Rapamycin Complex 2 - metabolism; metastasis; Mice; mTOR signaling; optogenetics; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; actin cytoskeleton; development; metastasis; optogenetics; immunotherapy; leukocytes; cancer; immunity; biochemical excitability; mTOR signaling
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2023.04.019

Ras signaling is typically associated with cell growth, but not direct regulation of motility or polarity. By optogenetically targeting different nodes in the Ras/PI3K/Akt network in differentiated human HL-60 neutrophils, we abruptly altered protrusive activity, bypassing the chemoattractant receptor/G-protein network. First, global recruitment of active KRas4B/HRas isoforms or a RasGEF, RasGRP4, immediately increased spreading and random motility. Second, activating Ras at the cell rear generated new protrusions, reversed pre-existing polarity, and steered sustained migration in neutrophils or murine RAW 264.7 macrophages. Third, recruiting a RasGAP, RASAL3, to cell fronts extinguished protrusions and changed migration direction. Remarkably, persistent RASAL3 recruitment at stable fronts abrogated directed migration in three different chemoattractant gradients. Fourth, local recruitment of the Ras-mTORC2 effector, Akt, in neutrophils or Dictyostelium amoebae generated new protrusions and rearranged pre-existing polarity. Overall, these optogenetic effects were mTORC2-dependent but relatively independent of PI3K. Thus, receptor-independent, local activations of classical growth-control pathways directly control actin assembly, cell shape, and migration modes. [Display omitted] •Global Ras activation directly increases random migration bypassing chemoattractants•Local Ras activity reverses polarity and steers migration via mTORC2-Akt activation•Local Ras inhibition blocks directed migration toward three different chemoattractants•Direct Akt activation improves polarity and migration, independently of PI3K activity Pal et al. uncover that chemoattractant receptor-independent, local activation of the Ras-mTORC2-Akt growth factor signal transduction network is directly required for actin organization, polarity, and directed migration in immune cells. Moreover, localized network activity is necessary for immune cell chemotaxis and may be considered essential for immune response signaling.