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Specific cancer-associated mutations in the switch III region of Ras increase tumorigenicity by nanocluster augmentation.

Šolman M, Ligabue A, Blaževitš O, Jaiswal A, Zhou Y, Liang H, Lectez B, Kopra K, Guzmán C, Härmä H, Hancock JF, Aittokallio T, Abankwa D - Elife (2015)

Bottom Line: Here, we show that several cancer-associated mutations in the switch III region moderately increase Ras activity in all isoforms.Nanoclustering dictates downstream effector recruitment, MAPK-activity, and tumorigenic cell proliferation.Our results describe an unprecedented mechanism of signaling protein activation in cancer.

View Article: PubMed Central - PubMed

Affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.

ABSTRACT
Hotspot mutations of Ras drive cell transformation and tumorigenesis. Less frequent mutations in Ras are poorly characterized for their oncogenic potential. Yet insight into their mechanism of action may point to novel opportunities to target Ras. Here, we show that several cancer-associated mutations in the switch III region moderately increase Ras activity in all isoforms. Mutants are biochemically inconspicuous, while their clustering into nanoscale signaling complexes on the plasma membrane, termed nanocluster, is augmented. Nanoclustering dictates downstream effector recruitment, MAPK-activity, and tumorigenic cell proliferation. Our results describe an unprecedented mechanism of signaling protein activation in cancer.

No MeSH data available.


Related in: MedlinePlus

Phylogenetic analysis of the Ras switch III region.(A) ClustalW sequence alignment of 18 Ras proteins from different species as annotated on the left. Consensus sequence is shaded in dark and switch III region elements β2-β3-loop (residues 40–56) and helix α5 (residues 152–166) are highlighted with a black frame. (B) Unrooted phylogenetic trees were built from these proteins for the β2-β3-loop and (C) helix α5. (B, C) Numbers on internal branches indicate the percentage of 1000 bootstrap trials that support the branch (numbers <70% are omitted). Residues outside the region of interest were excluded using the position-masking tool for both phylogenetic analyses. The analysis revealed that switch III residues are highly conserved among all analyzed Ras proteins. The human Ras isoforms cluster together with other Ras proteins from the Bilateria species (D. rerio, X. laevis, S. mansoni, M. edulis, D. melanogaster, and C. elegans). Ras proteins from the Fungi kingdom (S. pombe and T. hirsuta) and Cnidaria phylum (H. vulgaris) species show a divergent pattern that corresponds to the speciation events that occurred in the course of evolution (∼1298 Ma for Bilateria—Cnidaria and ∼1513 Ma for Animalia—Fungi speciation event) (Hedges et al., 2004).DOI:http://dx.doi.org/10.7554/eLife.08905.009
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fig3s1: Phylogenetic analysis of the Ras switch III region.(A) ClustalW sequence alignment of 18 Ras proteins from different species as annotated on the left. Consensus sequence is shaded in dark and switch III region elements β2-β3-loop (residues 40–56) and helix α5 (residues 152–166) are highlighted with a black frame. (B) Unrooted phylogenetic trees were built from these proteins for the β2-β3-loop and (C) helix α5. (B, C) Numbers on internal branches indicate the percentage of 1000 bootstrap trials that support the branch (numbers <70% are omitted). Residues outside the region of interest were excluded using the position-masking tool for both phylogenetic analyses. The analysis revealed that switch III residues are highly conserved among all analyzed Ras proteins. The human Ras isoforms cluster together with other Ras proteins from the Bilateria species (D. rerio, X. laevis, S. mansoni, M. edulis, D. melanogaster, and C. elegans). Ras proteins from the Fungi kingdom (S. pombe and T. hirsuta) and Cnidaria phylum (H. vulgaris) species show a divergent pattern that corresponds to the speciation events that occurred in the course of evolution (∼1298 Ma for Bilateria—Cnidaria and ∼1513 Ma for Animalia—Fungi speciation event) (Hedges et al., 2004).DOI:http://dx.doi.org/10.7554/eLife.08905.009

Mentions: The computational modeling-derived switch III residues D47 and E49 are phylogenetically highly conserved (Figure 3—figure supplement 1), consistent with a biologically significant role of their structural context. We hypothesized that if our link between the switch III and nanoclustering was physiologically relevant, genetic diseases with hyperactivated Ras, such as many cancers, should have exploited it to upregulate Ras-signaling activity.


Specific cancer-associated mutations in the switch III region of Ras increase tumorigenicity by nanocluster augmentation.

Šolman M, Ligabue A, Blaževitš O, Jaiswal A, Zhou Y, Liang H, Lectez B, Kopra K, Guzmán C, Härmä H, Hancock JF, Aittokallio T, Abankwa D - Elife (2015)

Phylogenetic analysis of the Ras switch III region.(A) ClustalW sequence alignment of 18 Ras proteins from different species as annotated on the left. Consensus sequence is shaded in dark and switch III region elements β2-β3-loop (residues 40–56) and helix α5 (residues 152–166) are highlighted with a black frame. (B) Unrooted phylogenetic trees were built from these proteins for the β2-β3-loop and (C) helix α5. (B, C) Numbers on internal branches indicate the percentage of 1000 bootstrap trials that support the branch (numbers <70% are omitted). Residues outside the region of interest were excluded using the position-masking tool for both phylogenetic analyses. The analysis revealed that switch III residues are highly conserved among all analyzed Ras proteins. The human Ras isoforms cluster together with other Ras proteins from the Bilateria species (D. rerio, X. laevis, S. mansoni, M. edulis, D. melanogaster, and C. elegans). Ras proteins from the Fungi kingdom (S. pombe and T. hirsuta) and Cnidaria phylum (H. vulgaris) species show a divergent pattern that corresponds to the speciation events that occurred in the course of evolution (∼1298 Ma for Bilateria—Cnidaria and ∼1513 Ma for Animalia—Fungi speciation event) (Hedges et al., 2004).DOI:http://dx.doi.org/10.7554/eLife.08905.009
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4563131&req=5

fig3s1: Phylogenetic analysis of the Ras switch III region.(A) ClustalW sequence alignment of 18 Ras proteins from different species as annotated on the left. Consensus sequence is shaded in dark and switch III region elements β2-β3-loop (residues 40–56) and helix α5 (residues 152–166) are highlighted with a black frame. (B) Unrooted phylogenetic trees were built from these proteins for the β2-β3-loop and (C) helix α5. (B, C) Numbers on internal branches indicate the percentage of 1000 bootstrap trials that support the branch (numbers <70% are omitted). Residues outside the region of interest were excluded using the position-masking tool for both phylogenetic analyses. The analysis revealed that switch III residues are highly conserved among all analyzed Ras proteins. The human Ras isoforms cluster together with other Ras proteins from the Bilateria species (D. rerio, X. laevis, S. mansoni, M. edulis, D. melanogaster, and C. elegans). Ras proteins from the Fungi kingdom (S. pombe and T. hirsuta) and Cnidaria phylum (H. vulgaris) species show a divergent pattern that corresponds to the speciation events that occurred in the course of evolution (∼1298 Ma for Bilateria—Cnidaria and ∼1513 Ma for Animalia—Fungi speciation event) (Hedges et al., 2004).DOI:http://dx.doi.org/10.7554/eLife.08905.009
Mentions: The computational modeling-derived switch III residues D47 and E49 are phylogenetically highly conserved (Figure 3—figure supplement 1), consistent with a biologically significant role of their structural context. We hypothesized that if our link between the switch III and nanoclustering was physiologically relevant, genetic diseases with hyperactivated Ras, such as many cancers, should have exploited it to upregulate Ras-signaling activity.

Bottom Line: Here, we show that several cancer-associated mutations in the switch III region moderately increase Ras activity in all isoforms.Nanoclustering dictates downstream effector recruitment, MAPK-activity, and tumorigenic cell proliferation.Our results describe an unprecedented mechanism of signaling protein activation in cancer.

View Article: PubMed Central - PubMed

Affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.

ABSTRACT
Hotspot mutations of Ras drive cell transformation and tumorigenesis. Less frequent mutations in Ras are poorly characterized for their oncogenic potential. Yet insight into their mechanism of action may point to novel opportunities to target Ras. Here, we show that several cancer-associated mutations in the switch III region moderately increase Ras activity in all isoforms. Mutants are biochemically inconspicuous, while their clustering into nanoscale signaling complexes on the plasma membrane, termed nanocluster, is augmented. Nanoclustering dictates downstream effector recruitment, MAPK-activity, and tumorigenic cell proliferation. Our results describe an unprecedented mechanism of signaling protein activation in cancer.

No MeSH data available.


Related in: MedlinePlus