Cracking the Phophatidylinositol 3-Kinase Signaling Code

Abstract

Tengholm and Meyer used dual-color evanescent wave microscopy, a technique that permits selective excitation of fluorophores in a resticted region of cell membrane, to investigate the relationship between phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) production and insertion of glucose transporters into the plasma membrane as a step toward deciphering the phosphatidylinositol 3-kinase (PI3K) signaling code.Various growth factors and hormones activate PI3K, which leads to PIP 3 production and numerous cellular responses. It is not clear how cells selectively activate the many possible sequelae of PIP 3 production so that stimulation of a particular receptor elicits the appropriate response. In adipocytes, insulin, which activates PI3K, triggers insertion of the glucose transporter GLUT4 into the plasma membrane; platelet-derived growth factor (PDGF), which also activates PI3K, is less efficient at stimulating GLUT4 insertion. Using GLUT4 labeled with yellow fluorescent protein and a cyan fluorescent protein-labeled construct that bound PIP 3 , Tengholm and Meyer simultaneously monitored PIP 3 production and GLUT4 insertion into the plasma membrane of 3T3L1 adipocytes. Insulin triggered PIP 3 production followed by GLUT4 insertion, as did relieving inhibition of a constitutively active PI3K derivative. Observation of a delay between PIP 3 production and GLUT4 insertion, which was greater at lower concentrations of PIP 3 , led the authors to determine a threshold of PIP 3 activity beneath which insertion was suppressed, which implied that small persistent signals or brief high-amplitude signals were ineffective in eliciting GLUT4 insertion. The authors proposed a model in which PI3K controlled specific cell functions that depended on effector systems sensitive to specific durations and amplitudes of the PIP 3 signal. A. Tengholm, T. Meyer, A PI3-kinase signaling code for insulin-triggered insertion of glucose transporters into the plasma membrane. Curr. Biol. 12 , 1871-1876 (2002). [Online Journal]