Biology Reference
In-Depth Information
17
Directional Sensing: Subcellular
Targeting of GPCR Downstream
Effectors During Chemotaxis
Satoru Funamoto
and
Richard A. Firtel
Directional cell movement mediated by an extracellular substance is called
chemotaxis, which is involved in various biological aspects such as wound
healing, metastasis in cancer, embryogenesis, morphogenesis and axonal
guidance. The formation of cell polarity is an initial event in chemotaxis. Cells
are able to polarize and to move up a gradient of chemoattractant as low as
2%, indicating that cells must amplify this extracellular gradient to produce
an asymmetrical distribution of regulatory information inside the cell.
Phosphoinositides (D3-PI) such as phosphatidylinositol(3,4,5)-trisphosphate
[PI(3,4,5)P
3
] and phosphatidylinositol(3,4)-bisphosphate [PI(3,4)P
2
], products
of phosphatidylinositol 3-kinases (PI3Ks), mediate the directional sensing and
the downstream establishment and maintenance of cell polarity. Cells in a
chemoattractant gradient locally accumulate PI(3,4,5)P
3
/PI(3,4)P
2
at the
leading edge, which results in the binding of a subfamily of cytosolic pleckstrin
homology (PH) domain-containing proteins to these lipid-enriched membrane
domains and the localized assembly of the actin machinery. Recently, we and
others defined the mechanisms controlling the spatial and temporal regulation
of the PI3Ks and the negative regulator, the phosphatidylinositol 3' phospha-
tase PTEN. In additional studies, we discovered that the Dictyostelium MAP
kinase kinase MEK1, which plays a key role in the establishment of cell
polarity and chemotaxis, also preferentially localizes to the leading edge. This
