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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

Nucleotide-dependent H-ras conformers on the membrane.Computational modeling-derived structures of the predominant H-ras-GTP- (left) and H-ras-GDP- (right) conformers on the membrane. Conformer stabilizing residues R128,R135 on helix α4 and R169,K170 in the hypervariable region (hvr), as well as switch III region residues of helix α5 (R161) and β2-β3-loop (D47,E49) are indicated. Color-coding as in Figure 1A.DOI:http://dx.doi.org/10.7554/eLife.08905.004
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fig1s1: Nucleotide-dependent H-ras conformers on the membrane.Computational modeling-derived structures of the predominant H-ras-GTP- (left) and H-ras-GDP- (right) conformers on the membrane. Conformer stabilizing residues R128,R135 on helix α4 and R169,K170 in the hypervariable region (hvr), as well as switch III region residues of helix α5 (R161) and β2-β3-loop (D47,E49) are indicated. Color-coding as in Figure 1A.DOI:http://dx.doi.org/10.7554/eLife.08905.004

Mentions: We previously revealed another aspect of Ras membrane organization, showing that a novel switch III in Ras is somehow coupled to the reorientation of H-ras on the membrane (Figure 1—figure supplement 1). Mutations in the switch III and the structural elements of H-ras that stabilize its reorientation (helix α4 and the C-terminal hypervariable region [hvr]) systematically modulate Ras signaling (Gorfe et al., 2007; Abankwa et al., 2008b, 2010). More recently, we addressed the mechanistic basis of this activity modulation for computational modeling-derived mutations on helix α4 and the hvr: these alter engagement of the nanocluster modulator Gal-1 and thus H-ras nanoclustering. As a consequence of this up-concentration, effector recruitment and subsequent downstream signaling are increased (Guzmán et al., 2014b).


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)

Nucleotide-dependent H-ras conformers on the membrane.Computational modeling-derived structures of the predominant H-ras-GTP- (left) and H-ras-GDP- (right) conformers on the membrane. Conformer stabilizing residues R128,R135 on helix α4 and R169,K170 in the hypervariable region (hvr), as well as switch III region residues of helix α5 (R161) and β2-β3-loop (D47,E49) are indicated. Color-coding as in Figure 1A.DOI:http://dx.doi.org/10.7554/eLife.08905.004
© Copyright Policy
Related In: Results  -  Collection

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

fig1s1: Nucleotide-dependent H-ras conformers on the membrane.Computational modeling-derived structures of the predominant H-ras-GTP- (left) and H-ras-GDP- (right) conformers on the membrane. Conformer stabilizing residues R128,R135 on helix α4 and R169,K170 in the hypervariable region (hvr), as well as switch III region residues of helix α5 (R161) and β2-β3-loop (D47,E49) are indicated. Color-coding as in Figure 1A.DOI:http://dx.doi.org/10.7554/eLife.08905.004
Mentions: We previously revealed another aspect of Ras membrane organization, showing that a novel switch III in Ras is somehow coupled to the reorientation of H-ras on the membrane (Figure 1—figure supplement 1). Mutations in the switch III and the structural elements of H-ras that stabilize its reorientation (helix α4 and the C-terminal hypervariable region [hvr]) systematically modulate Ras signaling (Gorfe et al., 2007; Abankwa et al., 2008b, 2010). More recently, we addressed the mechanistic basis of this activity modulation for computational modeling-derived mutations on helix α4 and the hvr: these alter engagement of the nanocluster modulator Gal-1 and thus H-ras nanoclustering. As a consequence of this up-concentration, effector recruitment and subsequent downstream signaling are increased (Guzmán et al., 2014b).

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