Ca2+/calmodulin binds and dissociates K-RasB from membrane

Sidhu, Ranjinder S.; Clough, Richard R.; Bhullar, Rajinder P.

doi:10.1016/s0006-291x(03)00635-1

Cited by 49 publications

(57 citation statements)

References 42 publications

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“…Calmodulin has an established role in destabilising protein electrostatic interactions with membranes, this is likely due to interactions with the basic cluster of amino acids inhibiting interactions with anionic lipids [55]. Calmodulin binds to the K(B)-Ras HVR and in rat hippocampal neurons promotes redistribution to the Golgi apparatus [57][58][59]. An alternative mechanism is provided by protein kinase C which phosphorylates K(B)-Ras on serine 181.…”

Section: Compartmentalisation Of Rasmentioning

confidence: 99%

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Omerovic

Laude

Prior

2007

Cell. Mol. Life Sci.

117

122

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Ras GTPases mediate a wide variety of cellular processes by converting a multitude of extracellular stimuli into specific biological responses including proliferation, differentiation and survival. In mammalian cells, three ras genes encode four Ras isoforms (H-Ras, K-Ras4A, KRas4B and N-Ras) that are highly homologous but functionally distinct. Differences between the isoforms, including their post-translational modifications and intracellular sorting, mean that Ras has emerged as an important model system of compartmentalised signalling and membrane biology. Ras isoforms in different subcellular locations are proposed to recruit distinct upstream and downstream accessory proteins and activate multiple signalling pathways. Here, we summarise data relating to isoform specific signalling, its role in disease and the mechanisms promoting compartmentalised signalling. Further understanding of this field will reveal the role of Ras signalling in development, cellular homeostasis and cancers and may suggest new therapeutic approaches.

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Section: Compartmentalisation Of Rasmentioning

confidence: 99%

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Omerovic

Laude

Prior

2007

Cell. Mol. Life Sci.

117

122

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“…Those authors also showed using W7, as an inhibitor of CaM activity, that this translocation was CaM-dependent and suggested that binding of CaM to the farnesyl group of K-Ras allows the release of K-Ras from the membrane and its intracellular translocation. Furthermore, it has been shown that CaM could dissociate K-Ras from membranes in vitro (20,47). The fact that the farnesyl group is an essential element for the interaction between CaM and K-Ras favors the hypothesis that CaM modulates interaction of K-Ras with the membranes.…”

mentioning

confidence: 99%

Identification of Essential Interacting Elements in K-Ras/Calmodulin Binding and Its Role in K-Ras Localization

López-Alcalá

Alvarez-Moya

Villalonga

et al. 2008

Journal of Biological Chemistry

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We previously showed that K-Ras is a calmodulin-binding protein. Involvement of this interaction in anterograde and retrograde transport of K-Ras was then suggested. To test this we have analyzed here the domains of K-Ras essential for the interaction with calmodulin. At least three different regions in the K-Ras molecule were important; they are the hypervariable region, the ␣-helix between amino acids 151 and 166, and the Switch II. Within the hypervariable region, both the hydrophobic farnesyl group and the positive-charged amino acids were essential for the interaction between K-Ras and calmodulin in cellular extracts. Consistently, K-Ras S181D, which mimics phosphorylation of Ser-181 of K-Ras, also completely abolished binding to calmodulin. K-Ras mutants correctly farnesylated that did not bind calmodulin were all located at plasma membrane, showing that calmodulin interaction was not required for the transport of K-Ras to plasma membrane. In NIH3T3 cells, K-Ras and calmodulin colocalized mainly in the plasma membrane even after the addition of Ca 2؉ ionophore, indicating that interaction did not directly lead to K-Ras internalization. Furthermore, using a K-Ras with impaired binding to calmodulin but with membrane localization, we could demonstrate in striatal neurones that interaction between K-Ras and calmodulin was not required for Golgi K-Ras translocation induced by Ca 2؉

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“…KRAS4B consists of a guanosine triphosphatase (GTPase) domain and a flexible, polybasic, farnesylated, C-terminal tail that anchors it to the PM. The KRAS4BeCaM interaction has been reported to be Ca 2þ -and GTP-dependent, and to involve the farnesyl group, the lysine-rich region and the GTPase domain [146e148], and is thought to reduce KRAS4B affinity for the PM [147,149,150]. KRAS4B depends upon basic residues in the tail for its dynamic membrane association [151,152], and protein kinase C (PKC) phosphorylation of a Ser in this region reduces the positive charge and leads to its redistribution to endomembranes [153] where it induces autophagy [154].…”

Section: Cam In Cancermentioning

confidence: 99%