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Spatiotemporal Organization of Ras Signaling: Rasosomes and the Galectin Switch

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Summary

1. Ras signaling and oncogenesis depend on the dynamic interplay of Ras with distinctive plasma membrane (PM) microdomains and various intracellular compartments. Such interaction is dictated by individual elements in the carboxy-terminal domain of the Ras proteins, including a farnesyl isoprenoid group, sequences in the hypervariable region (hvr)-linker, and palmitoyl groups in H/N-Ras isoforms.

2. The farnesyl group acts as a specific recognition unit that interacts with prenyl-binding pockets in galectin-1 (Gal-1), galectin-3 (Gal-3), and cGMP phosphodiesterase δ. This interaction appears to contribute to the prolongation of Ras signals in the PM, the determination of Ras effector usage, and perhaps also the transport of cytoplasmic Ras. Gal-1 promotes H-Ras signaling to Raf at the expense of phosphoinositide 3-kinase (PI3-K) and Ral guanine nucleotide exchange factor (RalGEF), while galectin-3 promotes K-Ras signaling to both Raf and PI3-K.

3. The hvr-linker and the palmitates of H-Ras and N-Ras determine the micro- and macro-localizations of these proteins in the PM and in the Golgi, as well as in ‘rasosomes’, randomly moving nanoparticles that carry palmitoylated Ras proteins and their signal through the cytoplasm.

4. The dynamic compartmentalization of Ras proteins contributes to the spatial organization of Ras signaling, promotes redistribution of Ras, and provides an additional level of selectivity to the signal output of this regulatory GTPase.

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Abbreviations

FRAP:

fluorescence recovery after photobleaching

G domain:

GTPase domain

Gal-1:

galectin-1

Gal-3:

galectin-3

GDIs:

guanine nucleotide-dissociation inhibitors

GFP:

green fluorescent protein

hvr:

hypervariable region

PI3-K:

phosphoinositide 3-kinase

PM:

plasma membrane

RalBD:

Ral-binding domain of Ral-binding protein 1

RasGAPs:

Ras GTPase-activating proteins

RalGEFs:

Ral guanine nucleotide exchange factors

RasGEFs:

Ras guanine nucleotide exchange factors

RBD:

Ras-binding domain of Raf-1

TIRF:

Total internal reflection fluorescence.

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ACKNOWLEDGEMENTS

We thank S.R. Smith for editorial assistance. Yoel Kloog is an incumbent of The Jack H. Skirball Chair in Applied Neurobiology. This work was supported in part by grants from The Israel Science Foundation Grants 339/02-3(YK) 424/02-16.6 (UA), the Wolfson Family Foundation Trust (YK), and the Minerva Junior Research Group (UA).

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  1. Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

    Uri Ashery, Ofer Yizhar, Barak Rotblat, Galit Elad-Sfadia, Batya Barkan, Roni Haklai & Yoel Kloog

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Ashery, U., Yizhar, O., Rotblat, B. et al. Spatiotemporal Organization of Ras Signaling: Rasosomes and the Galectin Switch. Cell Mol Neurobiol 26, 469–493 (2006). https://doi.org/10.1007/s10571-006-9059-3

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