A126 in the active site and TI167/168 in the TI loop are essential determinants of the substrate specificity of PTEN.

PTEN prevents tumor genesis by antagonizing the PI3 kinase/Akt pathway through D3 site phosphatase activity toward PI(3,4)P and PI(3,4,5)P. The structural determinants of this important specificity remain unknown. Interestingly, PTEN shares remarkable homology to voltage-sensitive phosphatases (VSPs) that dephosphorylate D5 and D3 sites of PI(4,5)P, PI(3,4)P, and PI(3,4,5)P.

Voltage sensitive phosphatases: emerging kinship to protein tyrosine phosphatases from structure-function research.

The transmembrane protein Ci-VSP from the ascidian Ciona intestinalis was described as first member of a fascinating family of enzymes, the voltage sensitive phosphatases (VSPs). Ci-VSP and its voltage-activated homologs from other species are stimulated by positive membrane potentials and dephosphorylate the head groups of negatively charged phosphoinositide phosphates (PIPs). In doing so, VSPs act as control centers at the cytosolic membrane surface, because they intervene in signaling cascades that are mediated by PIP lipids.

The linker pivot in Ci-VSP: the key to unlock catalysis.

In the voltage-sensitive phosphatase Ci-VSP, conformational changes in the transmembrane voltage sensor domain (VSD) are transduced to the intracellular catalytic domain (CD) leading to its dephosphorylation activity against membrane-embedded phosphoinositides. The linker between both domains is proposed to be crucial for the VSD-CD coupling. With a combined approach of electrophysiological measurements on Xenopus oocytes and molecular dynamics simulations of a Ci-VSP model embedded in a lipid bilayer, we analyzed how conformational changes in the linker mediate the interaction between the CD and the activated VSD.

Coupling of Ci-VSP modules requires a combination of structure and electrostatics within the linker.

The voltage-sensitive phosphatase Ci-VSP consists of an intracellular phosphatase domain (PD) coupled to a transmembrane voltage-sensor domain (VSD). Depolarization triggers the selective dephosphorylation of phosphoinositides. However, the molecular mechanisms of coupling are still elusive.

Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments.

Cytokines are pleiotropic and readily diffusible messenger molecules, raising the question of how their action can be confined to specific target cells. The T cell cytokine interleukin-2 (IL-2) is essential for the homeostasis of regulatory T (Treg) cells that suppress (auto)immunity and stimulates immune responses mediated by conventional T cells. We combined mathematical modeling and experiments to dissect the dynamics of the IL-2 signaling network that links the prototypical IL-2 producers, conventional T helper (Th) cells, and Treg cells.