Source: http://www.asmscience.org/content/book/10.1128/9781555816650.ch11
Timestamp: 2019-04-21 18:22:40+00:00

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The sequential and regulated recruitment of leukocytes into tissues by chemoattractants is essential for effective clearance of pathogens and healing. The Rho GTPases Cdc42, Rac, and Rho are important for establishing and maintaining migratory polarity. Most chemoattractants for phagocytes signal either through seven transmembrane G-protein-coupled receptors (GPCRs) or tyrosine kinase receptors. Y721 is the most important for chemotaxis because it recruits phospholipase-C-γ (PL C-γ) and the p85 subunit of class 1A PI3Ks, both of which are implicated in the initiation of chemotaxis. Several intracellular signaling complexes contribute to the polarization of phagocytes in response to chemoattractants, and they probably act together to allow optimal chemotaxis. Cdc42 is implicated in multiple types of cell polarity, including axon specification, yeast mating, and epithelial polarity. There are several PLC isoforms, of which PLCβ2 and PLCβ3 are activated by GPCR signaling in neutrophils, whereas PLCβ isoforms are activated by tyrosine kinase receptors. Polarity signals act to initiate polarization of cells, but subsequent maintenance of polarity could be achieved by Rac and Rho without the requirement for additional signals. Rho and Rac refine each other’s activity during cell polarization and migration, balancing actin polymerization, cell contraction, and adhesion essential for chemotaxis. Our current understanding of chemotaxis indicates that several signaling pathways act in concert to induce cell polarization, including Cdc42, Par proteins, PAK/PIX, and PI3Ks. The design and testing of inhibitors of signal transduction molecules involved in migration and chemotaxis will be an important goal for the future.
Rho GTPase signaling in migration and chemotaxis. (Top) Rho family GTPases cycle between an active GTP-bound conformation and an inactive GDP-bound conformation. This is regulated by RhoGEFs, which stimulate exchange of GDP for GTP, and RhoGAPs, which stimulate hydrolysis of GTP. When bound to GTP, Rho GTPases activate downstream effectors that mediate cellular responses. (Bottom) In migrating cells, Rac is active at the front of cells. Rac is required for lamellipodium extension. Rho activity is restricted mostly to the rear and is involved in generation of cell traction in the cell body and retraction of the tail or uropod.
GPCR-induced signaling in chemotaxis. Ligand binding to GPCRs activates heterotrimeric G proteins, leading to dissociation of Gα from Gβγ subunits. Gα and Gβγ each activate a variety of signaling pathways that contribute to cell migration. For example, Gα12/13 subunits can activate RhoGEFs to increase Rho activity at the rear, and Gβγ subunits activate PI3Kγ, which acts at the front of the cell to stimulate Rac.
CSF-1 receptor signaling in chemotaxis. Activation of the CSF-1 receptor results in homodimerization (not depicted) and autophosphorylation on several tyrosines. Phosphorylation of Y721 is probably most important for chemotaxis because it recruits PLC-γ and the p85 subunit of class 1A PI3Ks, both of which are implicated in the initiation of chemotaxis. Several other SH2-containing proteins are also recruited to the activated CSF-1 receptor including RhoGEFS and GAPs. KD, kinase domain.
Involvement of PI3Ks and PTEN in chemotaxis. PI3Ks are selectively active at the front of polarized migrating cells, whereas PTEN is primarily localized in the cytoplasm. Production of PIP3 by PI3Ks recruits proteins that have PH domains including the serine/threonine kinase AKT, RhoGEFs, and adaptor proteins such as Gab1, all of which transduce signals to cell motility and chemotaxis. PIP3 is removed by the phosphatase PTEN, which converts PIP3 to PI(4,5)P2.
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