Galectin-1 Augments Ras Activation and Diverts Ras Signals to Raf-1 at the Expense of Phosphoinositide 3-Kinase

Abstract

This demonstrates a novel mechanism controlling the duration and selectivity of the Ras signal. Ras gains selectivity when it is associated with galectin-1, mimicking the selectivity of Ras(T35S), which activates Raf-1 but not PI3K.

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

“…[37] Galectin-1 not only behaves as a key scaffold for the formation of H-Ras nanoclusters, it also functions as a molecular chaperone that contributes to H-Ras trafficking, by returning depalmitoylated H-Ras to the GC. [38] Ras activation and activities: When site matters Not unexpectedly, the presence of Ras at multiple sites has functional consequences that result both from particularities in the way Ras activation is regulated at distinct localizations and from quantitative and qualitative variability in the way Ras engages its effector pathways. Originally, guanine nucleotide exchange factors (GEFs) were thought to activate Ras exclusively at the PM.…”

“…[34] In addition, formation of Ras nanoclusters transforms analog signal input into digital output, [48] which may be related to the potentiation of cellular transformation by Galectin-1. [37,38] Importantly, Ras sublocalization markedly influences which effector pathways are activated and how intensively. Probably, this has a lot to do with the abundance and availability of effector molecules at different sites.…”

“…This notion also seems to hold at the ''nano'' scale: EGF stimulates Raf recruitment to K-Ras but not to H-Ras nanoclusters. [52] Effector usage can be influenced by site-specific regulatory proteins, as exemplified by Galectins: Galectin-1 diverts H-Ras signals to Raf-1 at the expense of PI3K, [38] whereas Galectin-3 attenuates ERK activation without affecting PI3K activity. [36] Ras trafficking can also impact on effector utilization.…”

K-Ras4B phosphorylation at Ser181 is inhibited by calmodulin and modulates K-Ras activity and function

“…And proteins, such as Galectin-1 and Galectin-3 have an important role to anchor Ras proteins to different plasma membrane microlocalizations, generating nanoclusters and regulating Ras segregation and function. Galectin-3 interacts with activated K-Ras through the hypervariable carboxyterminal region and stimulates KRas activity triggering a Ras signal that attenuates ERK, but not PI3K (Elad-Sfadia et al, 2002.…”

Galectin-3 Augments K-Ras Activation and Triggers a Ras Signal That Attenuates ERK but Not Phosphoinositide 3-Kinase Activity

“…Another important sign that Ras signaling selectivity can be achieved at the level of Ras-effector interactions comes from the observation that galectin-1, discovered originally as a ␤-galactoside-binding protein (20), interacts with activated HRas and K-Ras proteins and diverts the Ras signal toward Raf-1 and away from PI3-K (21,22). In addition, we observed in co-immunoprecipitation experiments that H-Ras(G12V) pulls down significantly more galectin-1 than K-Ras(G12V) (22). These experiments indicate that interactions of galectin-1 with H-Ras-GTP and with K-Ras-GTP are not identical.…”