Regulation of Ras localization by acylation enables a mode of intracellular signal propagation.
Growth factor stimulation generates transient H-Ras activity at the plasma membrane but sustained activity at the Golgi. Two overlapping regulatory networks control compartmentalized H-Ras activity: the guanosine diphosphate-guanosine triphosphate cycle and the acylation cycle, which constitutively traffics Ras isoforms that can be palmitoylated between intracellular membrane compartments. Quantitative imaging of H-Ras activity after decoupling of these networks revealed regulation of H-Ras activity at the plasma membrane but not at the Golgi. Nevertheless, upon stimulation with epidermal growth factor, Ras activity at the Golgi displayed a pulse-like profile similar to that at the plasma membrane but also remained high after the initial stimulus. A compartmental model that included the acylation cycle and H-Ras regulation at the plasma membrane accounted for the pulse-like profile of H-Ras activity at the Golgi but implied that sustained H-Ras activity at the Golgi required H-Ras activation at an additional compartment, which we experimentally determined to be the endoplasmic reticulum. Thus, in addition to maintaining the localization of Ras, the acylation cycle underlies a previously unknown form of signal propagation similar to radio transmission in its generation of a constitutive Ras "carrier wave" that transmits Ras activity between subcellular compartments.
Lorentzen
Anna
A
European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Kinkhabwala
Ali
A
Rocks
Oliver
O
Vartak
Nachiket
N
Bastiaens
Philippe I H
PI
D000215:Acylation; D000818:Animals; D002451:Cell Compartmentation / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D004285:Dogs; D004815:Epidermal Growth Factor / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism*
D004815:Epidermal Growth Factor; D018631:ras Proteins