Regulation of PTEN by Rho small GTPases

Zhong Li, et al. Nat Cell Biol, 7, 399-404, 2005

Speaker: 翁子玉                           Date:14:10~15:00, May 11, 2005

Commentator: 劉校生老師                   Place: Room 601

Abstract:

Rho family GTPases and G-protein-coupled receptor are the key effectors in chemotaxis. PTEN (phosphatase and tensin homologue), a tumor suppressor gene, plays important roles in regulating biological functions, including cell migration¹ and chemotaxis². The authors observed that PTEN colocalized with RhoA at the posterior of the chemotactic neutrophils, but not with the Cdc42 at the leading edge. They, therefore, proposed that RhoA activity may positively regulate PTEN to the cell’s posterior and Cdc42 excluded it from the leading edge. Consistently, their data confirmed that PTEN no longer polarized in α-PIX-deficient cells (αPIX/ Cdc42 pathway³ is essential for the migration of chemotactic leukocytes), in which Cdc42 activation is abrogated or after the treatment of Y-27632, an inhibitor of the RhoA effector Rock (RhoA-associated kinase) activity, suggesting that Cdc42 and Rock activity are important in PTEN localization. The authors utilizedPTEN-siRNA suppression and measured phosphorylation level of Akt. They revealed that Rho GTPases indeed can upregulate PTEN and its substrate PtdIn(3,4,5)P_3, which further phosphorylates Akt. They also identified the important residues on PTEN that were required for its regulation by the small GTPases. Furthermore, PTEN activation by RhoA was confirmed using the PTEN activity assay, and Rock could also directly phosphorylate PTEN in vitro. Here, the authors showed that PTEN was phosphorylated by Rock, then localized with RhoA and Rock to the back and sides of polarized cells under chemotactic conditions. α-PIX-Cdc42 pathway may also increase PTEN activity, possibly through the restriction of RhoA to the posterior of the cells. All together, this study provides new insight into small GTPase regulated PTEN’s function which has a significant role in the regulation of chemotaxis.

References:

1. Tamura, M. et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 280, 1614–1617 (1998).

2. Funamoto, S. et al. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell, 109, 611–623 (2002).

3. Li, Z. et al. Directional sensing requires G beta gamma-mediated PAK1 and α-PIX dependent activation of Cdc42. Cell, 114, 215–227 (2003).