Actuation of Single Downstream Nodes in Growth Factor Network Mediates Neutrophil Guidance
2022; RELX Group (Netherlands); Linguagem: Inglês
10.2139/ssrn.4295347
ISSN1556-5068
AutoresDhiman Sankar Pal, Tatsat Banerjee, Yiyan Lin, Jane Borleis, Peter N. Devreotes,
Tópico(s)Neutrophil, Myeloperoxidase and Oxidative Mechanisms
ResumoDownload This Paper Open PDF in Browser Add Paper to My Library Share: Permalink Using these links will ensure access to this page indefinitely Copy URL Actuation of Single Downstream Nodes in Growth Factor Network Mediates Neutrophil Guidance Developmental Cell 71 Pages Posted: 9 Dec 2022 Publication Status: Under Review See all articles by Dhiman PalDhiman PalJohns Hopkins University - Center for Cell DynamicsTatsat BanerjeeJohns Hopkins University - Center for Cell DynamicsYiyan LinJohns Hopkins University - Center for Cell DynamicsJane BorleisJohns Hopkins University - Center for Cell DynamicsPeter N. DevreotesJohns Hopkins University - Center for Cell Dynamics More... Abstract Functions of Ras oncogenes and their downstream effectors are typically associated with cell proliferation and growth control while their role in mammalian cell migration has been largely unexplored. Although Ras-mediated signaling cascades have been implicated in immune response, there is no evidence showing that local activation of these pathways directly regulates cell motility or polarity. By establishing optogenetic systems to trigger multiple different individual network nodes in human neutrophils, we were able to abruptly alter protrusive activity, bypassing the chemoattractant-sensing receptor/G-protein network. First, global recruitment of active KRas4B/HRas isoforms or the guanine nucleotide exchange factor, RasGRP4, immediately increased spreading and random motility in neutrophils. Second, creating Ras activity at the cell rear generated new protrusions at the site and reversed pre-existing polarity. Third, recruiting GTPase activating protein, RASAL3, at cell fronts abrogated existing protrusions and changed the direction of motility whereas dynamically inhibiting nascent fronts stopped migration completely. Fourth, combining pharmacological inhibition studies with optogenetics revealed that mTorC2 is more important than PI3K for Ras-mediated polarity and migration. Finally, local recruitment of Ras-mTorC2 effector, Akt, also generated new protrusions, rearranged pre-existing polarity, and triggered migration, even in absence of PI3K signaling. We propose that actin assembly, cell shape, and migration modes in neutrophils are controlled by spontaneous, receptor-independent local activations of downstream components of classical growth-control pathways. Note: Funding Information: This work was supported by NIH grant R35 GM118177 (to PND), DARPA HR0011-16-C-0139 (to PAI and PND), AFOSR MURI FA95501610052 (to PND), as well as NIH grant S10 OD016374 (to S Kuo of the JHU Microscope Facility). Declaration of Interests: The authors declare no competing interests. Keywords: biochemical excitability, cancer, leukocytes, inflammation, optogenetics Suggested Citation: Suggested Citation Pal, Dhiman and Banerjee, Tatsat and Lin, Yiyan and Borleis, Jane and Devreotes, Peter N., Actuation of Single Downstream Nodes in Growth Factor Network Mediates Neutrophil Guidance. Available at SSRN: https://ssrn.com/abstract=4295347 This version of the paper has not been formally peer reviewed. Dhiman Pal Johns Hopkins University - Center for Cell Dynamics Tatsat Banerjee Johns Hopkins University - Center for Cell Dynamics ( email ) Yiyan Lin Johns Hopkins University - Center for Cell Dynamics ( email ) Jane Borleis Johns Hopkins University - Center for Cell Dynamics ( email ) Peter N. Devreotes (Contact Author) Johns Hopkins University - Center for Cell Dynamics ( email ) Download This Paper Open PDF in Browser Please enable JavaScript to view the comments powered by Disqus. 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