Editors' ChoiceInsulin Signaling

Cracking the Phophatidylinositol 3-Kinase Signaling Code

Science's STKE  05 Nov 2002:
Vol. 2002, Issue 157, pp. tw403-TW403
DOI: 10.1126/stke.2002.157.tw403

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 (PIP3) 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 PIP3 production and numerous cellular responses. It is not clear how cells selectively activate the many possible sequelae of PIP3 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 PIP3, Tengholm and Meyer simultaneously monitored PIP3 production and GLUT4 insertion into the plasma membrane of 3T3L1 adipocytes. Insulin triggered PIP3 production followed by GLUT4 insertion, as did relieving inhibition of a constitutively active PI3K derivative. Observation of a delay between PIP3 production and GLUT4 insertion, which was greater at lower concentrations of PIP3, led the authors to determine a threshold of PIP3 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 PIP3 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]