Compartmentalized signalling of Ras

Abstract

Ras proteins associate with cellular membranes by virtue of a series of post-translational modifications of their C-terminal CAAX sequences. The discovery that two of the three enzymes that modify CAAX proteins are restricted to the endoplasmic reticulum led to the recognition that all nascent Ras proteins transit endomembranes en route to the PM (plasma membrane) and that at steady-state N-Ras and H-Ras are highly expressed on the Golgi apparatus. To test the hypothesis that Ras proteins on internal membranes can signal, we developed a fluorescent probe that reports when and where in living cells Ras becomes active. We found that growth factors stimulated rapid and transient activation of Ras on the PM followed by delayed and sustained activation on the Golgi. We mapped one pathway responsible for this activity as involving PLCgamma (phospholipase Cgamma)/DAG (diacylglycerol)+Ca2+/RasGRP1. Using mammalian cells and fission yeast, we have shown that differential localization of activated Ras preferentially activates distinct signalling pathways. In very recent work, we have found that (i) the subcellular localization of K-Ras can be acutely modulated by phosphorylation of its C-terminal hypervariable region by PKC, (ii) among the membranes upon which phosphorylated K-Ras accumulates is the outer mitochondrial membrane and (iii) phosphorylated, internalized K-Ras promotes apoptosis. Thus the signalling output of Ras depends on its subcellular localization.

Heterotrimeric G protein signaling in theArabidopsisunfolded protein response

“…Because IP 3 receptors are primarily in ER and other membranes, such as the Golgi, surrounding Ca 2ϩ stores (40), these are the most likely sites of physical interactions between G␤␥ and IP 3 receptors. In addition, the conventional view that G protein signaling is confined to the plasma membrane has begun to expand with evidence that Ras signaling occurs both in the plasma membrane and in the ER and Golgi (47). The concept that signaling interactions occur in intracellular compartments is particularly compatible with recent reports identifying intracellular plant hormone receptors, including the ER-localized ethylene receptor (34).…”

Competitive and Non-competitive Regulation of Calcium-dependent Inactivation in CaV1.2 L-type Ca2+ Channels by Calmodulin and Ca2+-binding Protein 1

“…1, C and D, upper panel schematic). To accomplish this we added a prenylation signal element to the carboxyl end of the NT (CAAX box originating from K-Ras) (56). For pCT, we added a myristoylation signal from Src (57) at the N-terminal end.…”

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

“…[8] More recently, thanks to the pioneering work of M. Philips, it was demonstrated that Ras was also present and active in endomembranes like the endoplasmic reticulum (ER) and the Golgi complex (GC). [9,10] The three Ras isoforms were also detected in endosomes [11,12] and mitochondria [13][14][15] (for a review see ref. 16).…”