Abstract
Ras is the most frequently mutated oncogene and recent drug development efforts have spurred significant new research interest. Here we review progress toward understanding how Ras functions in nanoscale, proteo-lipid signaling complexes on the plasma membrane, called nanoclusters. We discuss how G-domain reorientation is plausibly linked to Ras-nanoclustering and -dimerization. We then look at how these mechanistic features could cooperate in the engagement and activation of RAF by Ras. Moreover, we show how this structural information can be integrated with microscopy data that provide nanoscale resolution in cell biological experiments. Synthesizing the available data, we propose to distinguish between two types of Ras nanoclusters, an active, immobile RAF-dependent type and an inactive/neutral membrane anchor-dependent. We conclude that it is possible that Ras reorientation enables dynamic Ras dimerization while the whole Ras/RAF complex transits into an active state. These transient di/oligomer interfaces of Ras may be amenable to pharmacological intervention. We close by highlighting a number of open questions including whether all effectors form active nanoclusters and whether there is an isoform specific composition of Ras nanocluster.
Highlights
Ras proteins are small GTPases that are critical for central cellular signaling pathways such as MAPK and PI3K/mTORC1 pathway initiation, driving cell proliferation, differentiation and growth
Combining all of the data discussed in the previous sections, we propose that the selective engagement of a given Ras protein and an effector is determined by several factors
This thermodynamic gate constitutes a first level of specialization for Ras-effector coupling, potentially separating distinct effectors such as RAF and PI3K
Summary
Ras proteins are small GTPases that are critical for central cellular signaling pathways such as MAPK and PI3K/mTORC1 pathway initiation, driving cell proliferation, differentiation and growth. GTP-binding to Ras enables a critical conformational change primarily in its switch I and II regions [1] This is a prerequisite for Ras to engage its downstream effectors, such as RAF, which initiates the MAPK cascade, or PI3K, which kicks-off the mTORC1 pathway [2]. TJoRhans pHraontecioncskaarendnocno-lrleaangduoems lpyrdovisitdriebduotende ionf tthhee pfilrasstmpaiemceesmofberavnide,enancedftohrastuthchesseigsno-aclainllgedranftasn, oschlouwstienrgs othf aRtaRs aasrepnroecteeisnssarayrefonroRna-sr/aMndAoPmKlysigdnisatlroibuutpteudt [in12t,h13e].pBlaassmeda omnetmhebirrainneit,iaalnfidntdhiantgtsh, ethseeysod-ecfianlleedd ensasneonctilaulshtearlslmofaRrkassoafrea nReacsenssaanroycflourstRears[/1M4,A15P]K: signal output [12,13] Based on their initial findings, they defined essential hallmarks of a Ras nanocluster [14,15]:. Zooming into a Ras Nanocluster—Insight from Electron Microscopy (EM), Single Molecule Imaging, and Förster Resonance Energy Transfer (FRET) Studies
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