Calmodulin binding to the small GTPase Ral requires isoprenylated Ral

Sidhu, Ranjinder S.; Elsaraj, Sherif M; Grujic, Ognjen; Bhullar, Rajinder P.

doi:10.1016/j.bbrc.2005.08.053

Cited by 14 publications

(10 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…necessary for CaM interaction (62,63). Moreover, Ral and CaM interaction is disrupted by removal of the C-terminal Ral isoprenylated moiety, which is modified through geranylgeranylation, as in Rac1 (64). As demonstrated for other CaMBPs, we show here that post-translational modification and proximity of positively charged amino acids are involved in the binding of Rac1 to CaM.…”

Section: Rac1 and Cam Interactionsupporting

confidence: 63%

Rac1 and Calmodulin Interactions Modulate Dynamics of ARF6‐Dependent Endocytosis

Vidal-Quadras

Gelabert-Baldrich

Soriano-Castell

et al. 2011

Traffic

View full text Add to dashboard Cite

The main cellular Ca 2+ sensor, calmodulin (CaM), interacts with and regulates several small GTPases, including Rac1. The present study revealed high binding affinity of Rac1 for CaM and uncovered two new essential binding domains in Rac1: the polybasic region, important for phosphatidylinositol-4-phosphate 5-kinase (PIP5K) interaction, and the adjacent prenyl group. CaM inhibition increased Rac1 binding to PIP5K and induced an extensive phosphatidylinositol 4,5-bisphosphate (PI4,5P 2 )-positive tubular membrane network. Immunofluorescence demonstrated that the tubules were plasma membrane invaginations resulting from an ADP-ribosylation factor 6 (ARF6)-dependent and clathrin-independent pathway. The role of Rac1 in this endocytic route was analyzed by expressing constitutively active and inactive mutants. While active Rac1 impaired tubulation, the inactive mutant enhanced it. Intriguingly, inactive mutant expression elicited tubulation by recruiting PIP5K and inhibiting Rac1 at the plasma membrane. Accordingly, CaM inhibition inactivated Rac1 and increased Rac1/PIP5K interaction. Therefore, our findings highlight an important new role for Rac1 and CaM in controlling clathrin-independent endocytosis.

show abstract

Section: Rac1 and Cam Interactionsupporting

confidence: 63%

Rac1 and Calmodulin Interactions Modulate Dynamics of ARF6‐Dependent Endocytosis

Vidal-Quadras

Gelabert-Baldrich

Soriano-Castell

et al. 2011

Traffic

View full text Add to dashboard Cite

show abstract

“…Plasma membrane association of Ras proteins requires posttranslational modification such as geranylgeranylation [47] and C-terminal farnesylation. Here we demonstrated that the farnesylation of K-RasB is important for its specific interaction with Ca 2+ /CaM.…”

Section: Discussionmentioning

confidence: 99%

Both the C-Terminal Polylysine Region and the Farnesylation of K-RasB Are Important for Its Specific Interaction with Calmodulin

Liao

et al. 2011

PLoS ONE

View full text Add to dashboard Cite

BackgroundRas protein, as one of intracellular signal switches, plays various roles in several cell activities such as differentiation and proliferation. There is considerable evidence showing that calmodulin (CaM) binds to K-RasB and dissociates K-RasB from membrane and that the inactivation of CaM is able to induce K-RasB activation. However, the mechanism for the interaction of CaM with K-RasB is not well understood.Methodology/Principal FindingsHere, by applying fluorescence spectroscopy and isothermal titration calorimetry, we have obtained thermodynamic parameters for the interaction between these two proteins and identified the important elements of K-RasB for its interaction with Ca2+/CaM. One K-RasB molecule interacts with one CaM molecule in a GTP dependent manner with moderate, micromolar affinity at physiological pH and physiologic ionic strength. Mutation in the polybasic domain of K-Ras decreases the binding affinity. By using a chimera in which the C-terminal polylysine region of K-RasB has been replaced with that of H-Ras and vice versa, we find that at physiological pH, H-Ras-(KKKKKK) and Ca2+/CaM formed a 1∶1 complex with an equilibrium association constant around 105 M−1, whereas no binding reaction of K-RasB-(DESGPC) with Ca2+/CaM is detected. Furthermore, the interaction of K-RasB with Ca2+/CaM is found to be enhanced by the farnesylation of K-RasB.Conclusions/SignificanceWe demonstrate that the polylysine region of K-RasB not only contributes importantly to the interaction of K-RasB with Ca2+/CaM, but also defines its isoform specific interaction with Ca2+/CaM. The farnesylation of K-RasB is also important for its specific interaction with Ca2+/CaM. Information obtained here can enhance our understanding of how CaM interacts with K-RasB in physiological environments.

show abstract

“…A basic/hydrophobic amino acid‐rich region that forms an amphipathic α ‐helix is found in the C‐terminal region of RalA which has been shown to bind with calmodulin. A recent study has shown that both RalA and RalB have calcium‐dependent calmodulin‐binding sites in their C‐terminal domains as well as calcium‐independent‐binding sites in their N‐terminals . The highly variable regions of RalA and RalB with 50% identity are in the C‐terminal membrane‐targeting sequence ending with a CAAX tetrapeptide sequence .…”

Section: Ral Proteins and Their Structurementioning

confidence: 99%

Ral signaling pathway in health and cancer

et al. 2017

View full text Add to dashboard Cite

The Ral (Ras‐Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.

show abstract

Calmodulin binding to the small GTPase Ral requires isoprenylated Ral

Cited by 14 publications

References 22 publications

Rac1 and Calmodulin Interactions Modulate Dynamics of ARF6‐Dependent Endocytosis

Rac1 and Calmodulin Interactions Modulate Dynamics of ARF6‐Dependent Endocytosis

Both the C-Terminal Polylysine Region and the Farnesylation of K-RasB Are Important for Its Specific Interaction with Calmodulin

Ral signaling pathway in health and cancer

Contact Info

Product

Resources

About