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

Dhiman Sankar Pal; Tatsat Banerjee; Yiyan Lin; Félix de Trogoff; Jane Borleis; Pablo A Iglesias; Peter N Devreotes

doi:10.1016/j.devcel.2023.04.019

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

Dev Cell. 2023 Jul 10;58(13):1170-1188.e7. doi: 10.1016/j.devcel.2023.04.019. Epub 2023 May 22.

Authors

Dhiman Sankar Pal¹, Tatsat Banerjee², Yiyan Lin³, Félix de Trogoff⁴, Jane Borleis⁵, Pablo A Iglesias⁶, Peter N Devreotes⁷

Affiliations

¹ Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. Electronic address: dhimanpal8@gmail.com.
² Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA.
³ Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Mechanical Engineering, STI School of Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁶ Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁷ Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. Electronic address: pnd@jhmi.edu.

PMID: 37220748
PMCID: PMC10524337 (available on 2024-07-10)
DOI: 10.1016/j.devcel.2023.04.019

Abstract

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.

Keywords: actin cytoskeleton; biochemical excitability; cancer; development; immunity; immunotherapy; leukocytes; mTOR signaling; metastasis; optogenetics.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Movement / physiology
Dictyostelium* / metabolism
Humans
Intercellular Signaling Peptides and Proteins
Mechanistic Target of Rapamycin Complex 2 / metabolism
Mice
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt* / metabolism

Substances

Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
Mechanistic Target of Rapamycin Complex 2
Intercellular Signaling Peptides and Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding