Molecular mechanisms of polarity establishment in T cells.

摘要

The establishment of cell polarity is essential for the formation and function of higher organisms. The mechanisms that cells utilize to polarize in the direction of external signals are not understood. Helper T cells rapidly polarize towards cognate antigen presenting cells. Here we demonstrate that in T cells the small monomeric GTPase CDC42 coordinates the polarization of both the actin and tubulin cytoskeletons. GDP-bound CDC42 is found diffusely in the cytosol. Upon binding GTP, CDC42 re-localizes to punctate aggregates that are capable of forming peripheral patches at the cell membrane. This suggests that CDC42 may mediate the positional information of the APC by being activated in a spatially restricted manner. The coordination of the polarization of both cytoskeletons bifurcates at the level of CDC42. CDC42 initiates the re-orientation of the tubulin cytoskeleton microtubule organizing center through residues 35 and 40 within the canonical effector domain. This signaling pathway may involve the activity of a Pak kinase. The actin rearrangements are stimulated through a second, presently undefined, domain of CDC42. This pathway requires the activity of another small GTPase, Rac1, perhaps recaptiulating a GTPase cascade. As these molecules are highly conserved, and the process of polarization itself is conserved, the pathway identified in this study may be broadly utilized.