An Acylation Cycle Regulates Localization and Activity of Palmitoylated Ras Isoforms

Abstract

We show that the specific subcellular distribution of H- and Nras guanosine triphosphate-binding proteins is generated by a constitutive de/reacylation cycle that operates on palmitoylated proteins, driving their rapid exchange between the plasma membrane (PM) and the Golgi apparatus. Depalmitoylation redistributes farnesylated Ras in all membranes, followed by repalmitoylation and trapping of Ras at the Golgi, from where it is redirected to the PM via the secretory pathway. This continuous cycle prevents Ras from nonspecific residence on endomembranes, thereby maintaining the specific intracellular compartmentalization. The de/reacylation cycle also initiates Ras activation at the Golgi by transport of PM-localized Ras guanosine triphosphate. Different de/repalmitoylation kinetics account for isoform-specific activation responses to growth factors.

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

“…Inhibition of the palmitoylation/de-palmitoylation cycle prevented accumulation and activation of H-Ras on the Golgi [64]. In this model Ras activation stimulates depalmitoylation and traffic to the Golgi where a new and distinct pool of effectors may be subsequently activated.…”

“…Several advanced fluorescence based approaches [89]. Some studies have revealed endomembrane Ras activation in addition to the cell surface pool [64,[90][91][92][93], whilst others only detect plasma membranelocalised Ras activation [94][95][96]. One criticism of the evidence for endomembranous Ras activation is that it is normally seen only with over-expression of Ras.…”

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

“…2). [25,26] Non-palmitoylated K-Ras4B also traffics back and forth from the PM, although by other mechanisms: phosphorylation of K-Ras4B by PKC promotes its release from the PM and its transfer to mitochondria. [27] Calmodulin binding to K-Ras4B also dislodges it from the PM, facilitating its translocation to the GC and to early endosomes.…”

Quantitative microscopy and systems biology: seeing the whole picture

“…These isoforms of Ras diVer mainly in their C-terminal membrane anchors that determine cellular localization and micro-localization within membranes (Rocks et al 2006). For instance, within the whole cell an acylation cycle dynamically partitions H-Ras between the plasma membrane and the Golgi (Rocks et al 2005). On the other hand K-Ras is not subject to such an acylation cycle but its association with the plasma membrane is regulated via phosphorylation (Bivona et al 2006).…”