Ras/MAPK signaling from endomembranes

Abstract

Signal transduction along the Ras/MAPK pathway has been generally thought to take place at the plasma membrane. It is now evident that the plasma membrane is not the only platform capable of Ras/MAPK signal induction. Fusion of Ras with green fluorescent protein and the development of genetically encoded fluorescent probes for Ras activation have revealed signaling events on a variety of intracellular membranes including endosomes, the Golgi apparatus and the endoplasmic reticulum. Thus, the Ras/MAPK pathway is spatially compartmentalized within cells and this may afford greater complexity of signal output.

Figure 1

Post‐translational modification and trafficking of Ras. Ras proteins are synthesized in the cytosol where their CAAX C‐terminal sequence is recognized by farnesyltransferase. The farnesylated proteins are sent to the endoplasmic reticulum (ER) where they encounter Ras converting enzyme (Rce1) and isoprenylcysteine carboxyl methyltransferase (Icmt) that subsequently remove the AAX amino acids and methyl esterify the α carboxyl group. From here K‐Ras is sent directly to the plasma membrane (PM) but N‐Ras and H‐Ras travel to the Golgi where they are modified with one or two palmitates before being sent on to the PM. K‐Ras recycles back to endomembranes as a consequence of phosphorylation by PKC on serine 181 or through the action of calmodulin. N‐Ras and H‐Ras recycle back to the Golgi as a consequence of depalmitoylation at the PM. Reprinted, with permission, from the Annual Review of Immunology, Volume 24 ©2006 by Annual Reviews, www.annualreviews.org.

Figure 2

Ras signaling from endomembranes. N‐Ras and H‐Ras decorate the cytoplasmic surface of EEA1+/Rab5+/PI3P+ early endosomes (EE) as a consequence of endocytosis and, when diubiquitinated (Ub), are retained on this compartment. Alternatively they can be recycled to the plasma membrane (PM), perhaps via Rab11+ recycling endosomes (RE). APPL1+/PI3P‐ signaling endosomes (SE) that derive from and can be returned to the bulk pool of EEs have recently been described that are competent for MAPK signaling but have not yet been examined for Ras. N‐Ras and H‐Ras also cycle between the PM and Golgi as a consequence of a palmitoylation/depalmitoylation cycle traveling anterograde on secretory vesicles (SV) and retrograde via diffusion. K‐Ras also decorates various endosomes, including Lamp1/2+/Rab7+ late endosomes (LE) and multivesicular bodies (MVB), although it remains unclear whether this is a consequence of endocytosis as opposed to transport to the organelle from the PM via the cytosol. K‐Ras phosphorylated at the PM by PKC translocates to the outer surface of mitochondria as well as to Golgi and ER. Solid black tails on Ras proteins depict the farnesyl modification, green tails represent palmitates and +++ designates the polybasic region of K‐Ras.