QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online February 20, 2008
doi: 10.1242/10.1242/jcs.023333

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kölsch, V. Articles by Firtel, R. A. Search for Related Content PubMed PubMed Citation Articles by Kölsch, V. Articles by Firtel, R. A.

The regulation of cell motility and chemotaxis by phospholipid signaling

Section of Cell and Developmental Biology, Division of Biological Sciences, Center for Molecular Genetics, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0380, USA

View larger version (22K): [in this window] [in a new window]   Fig. 1. PtdIns(3,4,5)P3 (PIP3) controls cell motility. Basic cell motility is regulated by a Ras–PI3K–PtdIns(3,4,5)P3–F-actin circuit. During chemotaxis, this circuit becomes restricted to the leading edge, allowing directed movement. Several downstream effectors of PtdIns(3,4,5)P3, 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)P3 (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).

View larger version (25K): [in this window] [in a new window]   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)P2 (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; Gβ, heterotrimeric G protein; cAR1, cAMP receptor; PIP3, PtdIns(3,4,5)P3.

View larger version (29K): [in this window] [in a new window]   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)P2 (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)P3; SSH, Slingshot.