spacer gif spacer gif spacer gif spacer gif spacer gif
QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents    

First published online July 31, 2003
doi: 10.1242/10.1242/jcs.00703

This Article
Right arrow Summary Freely available
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Merlot, S.
Right arrow Articles by Firtel, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Merlot, S.
Right arrow Articles by Firtel, R. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Leading the way: directional sensing through phosphatidylinositol 3-kinase and other signaling pathways

Sylvain Merlot and Richard A. Firtel*

Section of Cell and Developmental Biology, Division of Biological Sciences and Center for Molecular Genetics, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0634, USA



View larger version (26K):

[in a new window]
  		Fig. 1. PH domain and PI3K localization. The upper panel illustrates the temporal localization of the PH-domain-containing protein PhdA to the plasma membrane in response to a directional signal. In the first panel (left), the micropipette (asterisk) is in the upper right-hand corner and there is a localization of the protein in the part of the cell closest to the micropipette. In the second panel, the micropipette has moved, leading to a delocalization of PhdA from the original site and localization to the new position of the micropipette (panel 3). The fourth panel (right) indicates that when the micropipette is moved again, there is once again a delocalization of PhdA from the old site and a relocalization to the new site of the micropipette. The lower panels illustrate a similar dynamic localization of PI3K to the position on the plasma membrane closest to the chemoattractant source. The first panel shows the localization on the right side of the cell. When the micropipette is moved, there is a loss of this localization and a relocalization to the new position on the membrane. This localization is not sensitive to latrunculin A (data not shown), indicating that it is not dependent on the actin cytoskeleton.

 


View larger version (19K):

[in a new window]
  		Fig. 2. Model for activation of PI3K during chemotaxis. Chemoattractant binding on a G-protein-coupled-receptor (GPCR) leads to the translocation and activation of Class I PI3Ks at the plasma membrane. This activation mechanism that requires both G protein and Ras GTPase remains poorly understood at the molecular level. Activated PI3K catalyzes the phosphorylation of PtdIns(4,5)P2 at the 3' position of the inositol ring to produce PtdIns(3,4,5)P3. In response, PtdIns(3,4,5)P3 acts as a binding site for a subclass of PH domain proteins. These localize to the plasma membrane and are activated. In neutrophils, Rho family GEFs such as P-Rex are PI3K effectors, which lead to the accumulation of activated Rac (Rac-GTP). The feedback loop required for the amplification of the pathway may involve actin polymerization. In Dictyostelium, the delocalization of PTEN from the plasma membrane at the leading edge may function as an amplification pathway for PI3K signaling by preferentially extending the half-life of PtdIns(3,4,5)P3 at this site of the membrane.

 


View larger version (37K):

[in a new window]
  		Fig. 3. Spatial-temporal regulation of PTEN and PI3K induces cell polarization in response to a chemoattractant signal. (A) In unstimulated cells, Class I PI3K is mainly cytoplasmic, whereas PTEN is localized at the plasma membrane, resulting in a homogenous distribution of PtdIns(4,5)P2 in the plasma membrane. (B) When cells sense the chemoattractant signal, a signaling pathway yet to be identified promotes the rapid PI3K translocation to the leading edge facing the higher chemoattractant concentration and the delocalization of PTEN from the leading edge. Therefore, PtdIns(3,4,5)P3 is synthesized from PtdIns(4,5)P2 at the leading edge and prevented from accumulating on the sides and at the back of the cell by PTEN, causing a very steep anterior/posterior PtdIns(3,4,5)P3 gradient. (C) PtdIns(3,4,5)P3 recruits and activates at the leading edge RhoGEF proteins and other PH domain-containing proteins. The activity of these proteins is important to stimulate the actin polymerization necessary for cell motility. In coordination with these events in the leading edge, signaling by one or more pathways that remain to be identified restricts certain proteins to the back of the cell. These proteins are important for inhibiting pseudopod protrusion from the sides of the cell and for retracting the back of the cell while the leading edge is moving forward.

 

Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?



© The Company of Biologists Ltd 2003