The regulation of cell motility and chemotaxis by phospholipid signaling - PubMed (original) (raw)

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The regulation of cell motility and chemotaxis by phospholipid signaling

Verena Kölsch et al. J Cell Sci. 2008.

Abstract

Phosphoinositide 3-kinase (PI3K), PTEN and localized phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] play key roles in chemotaxis, regulating cell motility by controlling the actin cytoskeleton in Dictyostelium and mammalian cells. PtdIns(3,4,5)P3, produced by PI3K, acts via diverse downstream signaling components, including the GTPase Rac, Arf-GTPases and the kinase Akt (PKB). It has become increasingly apparent, however, that chemotaxis results from an interplay between the PI3K-PTEN pathway and other parallel pathways in Dictyostelium and mammalian cells. In Dictyostelium, the phospholipase PLA2 acts in concert with PI3K to regulate chemotaxis, whereas phospholipase C (PLC) plays a supporting role in modulating PI3K activity. In adenocarcinoma cells, PLC and the actin regulator cofilin seem to provide the direction-sensing machinery, whereas PI3K might regulate motility.

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Figures

Fig. 1

Fig. 1

PtdIns(3,4,5)_P_3 (PIP3) controls cell motility. Basic cell motility is regulated by a Ras–PI3K–PtdIns(3,4,5)_P_3–F-actin circuit. During chemotaxis, this circuit becomes restricted to the leading edge, allowing directed movement. Several downstream effectors of PtdIns(3,4,5)_P_3, such as RacGEFs and Akt, activate F-actin polymerization and myosin assembly (see text for details). Positive-feedback loops (red arrows) allow signal amplification, enhanced actin polymerization at the leading edge and the production of pseudopodia. In addition, Ras effectors, such as TORC2 (target of rapamycin complex 2), regulate the actin cytoskeleton and myosin assembly independently of PI3K and PtdIns(3,4,5)_P_3 (Lee et al., 2005). TORC2 functions, in part, by phosphorylating Akt in the C-terminal hydrophobic domain (Bhaskar and Hay, 2007). In Dictyostelium, Akt is thus regulated by two Ras-mediated pathways, PI3K and TORC2 (Lee et al., 2005).

Fig. 2

Fig. 2

PLA2 and PI3K/PTEN regulate chemotaxis in Dictyostelium. In Dictyostelium, chemotaxis is regulated by at least two intertwined and partly redundant pathways involving PI3K and PLA2. Both pathways are regulated by extracellular cAMP. The PI3K pathway is regulated, via PtdIns(4,5)_P_2 (PIP2)/PTEN, by PLC. The PLA2 pathway depends on cytosolic Ca2+, which is regulated by IP3 (thus partly by PLC), fatty acids and Ca2+ uptake. In steep gradients, either pathway is dispensable; in shallow gradients, both pathways are necessary to allow efficient chemotaxis (see text for details). Red arrows indicate enzymatic reactions. PL, phospholipids; Lyso-PL, lyso-phospholipids; Gαβγ, heterotrimeric G protein; cAR1, cAMP receptor; PIP3, PtdIns(3,4,5)_P_3.

Fig. 3

Fig. 3

PLC and cofilin are the gradient-sensing machinery in adenocarcinoma cells. In response to EGF stimulation, PLC becomes activated. By hydrolyzing PtdIns(4,5)_P_2 (PIP2), it activates cofilin. By severing actin filaments, cofilin increases the number of free barbed ends, producing the platform for the Arp2/3 complex and Ena/VASP proteins. This allows initial protrusion and determines the direction of movement. Activation of PI3K via EGF and its signaling to Arp2/3 promotes the formation of a stable lamellipod and efficient migration (see text for details). The phosphatase SSH and 14-3-3 proteins might be involved in regulating the phosphorylation state of cofilin. Red arrows indicate enzymatic reactions. EGFR, epidermal growth factor receptor; PIP3, PtdIns(3,4,5)_P_3; SSH, Slingshot.

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