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Integration of calcium and RAS signalling
Nature Reviews Molecular Cell Biologyvolume 3, pages339–348 (2002)Cite this article
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Key Points
Calcium (Ca2+) is a universal second messenger that is involved in the regulation of fertilization, secretion, contraction, cell-cycle progression, cell proliferation, apoptosis, learning and memory. Intracellular, free Ca2+ concentrations are kept low and change dynamically due to release/re-uptake from intracellular stores, or entry/efflux across the plasma membrane.
Coordinated regulation of intracellular release and extracellular influx of Ca2+ sets up highly complex Ca2+ signals in terms of amplitude, frequency, duration and spatial patterning.
Ras is a small GTPase that cycles between a GTP-bound active conformation and a GDP-bound inactive conformation. Activation is dependent on the action of guanine nucleotide-exchange factors (GEFs); deactivation depends on the action of GTPase activating proteins (GAPs). Oncogenic Ras is locked in the GTP-bound form.
The extent of Ras activation is dependent on the balance between GEF and GAP activity. GEFs and GAPs might be stimulated, or inhibited, to modulate Ras-GTP levels during cell stimulation.
Active Ras stimulates a series of effector pathways, such as the mitogen-activates protein kinase (MAPK) cascade.
The localization of Ras, GEFs, GAPs and effector proteins is a key concept for Ras-dependent signalling. Many of these events are initiated at the inner leaflet of plasma membrane, where Ras is targeted by post-translational modification.
Ras guanine nucleotide-releasing factors (GRFs) are Ca2+-dependent Ras GEFs. Ca2+–calmodulin modulates Ras-GRF1 activity, and the function of this GEF seems to be particularly important in the central nervous system, in which Ca2+ signalling is crucial for learning and memory. Ras-GRF2 is more widely expressed and is also sensitive to changes in intracellular Ca2+. Evidence is accumulating that these proteins are bifunctional GEFs that also activate members of the Rho GTPase family.
The Ras guanine nucleotide-releasing factors (GRPs)/CalDAG-GEFs constitute a second family of Ras GEFs. Five members of the family have been discovered that vary in their substrate specificity and mechanism of regulation. All members have some activity towards Ras GTPases (H-Ras, K-Ras and N-Ras), at leastin vitro, but several also activate Rap1. Diacylglycerol (DAG) regulates all family members through a C1 domain, however they also contain EF-hands, and Ras GRP, CalDAG-GEFI and Ras GRP2 are regulated by Ca2+.
p120 Ras GAP is known to translocate to the plasma membrane, and be potentially activated, during Ca2+ signalling — although the mechanisms for translocation are not entirely clear.
CAPRI (Ca2+-promoted Ras inactivator) is a Ca2+-sensitive Ras GAP with little basal GAP activity in the resting cell. After Ca2+ elevation, CAPRI translocates to the plasma membrane through tandem C2 domains to deactivate Ras.
Neuronal cells are a particularly good example of how Ca2+ signals are coupled in space and time to Ras-MAPK regulation, although there is still much to unravel. Non-neuronal cells are less well understood in terms of Ca2+-dependent Ras-MAPK signalling.
The importance of frequency- and amplitude-dependent Ca2+ signalling for gene transcription has been shown, but is technically very difficult in terms of the Ras-MAPK cascade, or other effector pathways, to determine how complex Ca2+ signals influence Ras and downstream effectors.
For any mechanism of cell stimulation, there is an extremely complex series of events that can lead to Ras-MAPK stimulation. The influence of Ca2+ occurs at many levels, such as by phosphorylation events due to PYK2, Src family members and protein kinase C. An important challenge is to put the regulation of Ca2+-dependent GEFs and GAPs in context with the rest of the Ras regulatory machinery during appropriate cell stimulation.
The discovery of PLCɛ as a new Ras effector adds further complexity, as PLC signalling might be upstream and downstream of Ras activation.
New FRET (fluorescent resonance energy transfer)-based techniques for measuring the Ras activation state in a single cell might answer the question as to whether the activation state of Ras fluctuates in concert with Ca2+ oscillations. If Ras is proven to oscillate during Ca2+-signal frequency, then this has an important impact on the interpretation of downstream effector pathway stimulation and gene transcription.
Abstract
Calcium is a universal intracellular signal that is responsible for controlling a plethora of cellular processes. Understanding how such a simple ion can regulate so many diverse cellular processes is a key goal of calcium- and cell-biologists. One molecule that is sensitive to changes in intracellular calcium levels is Ras. This small GTPase operates as a binary molecular switch, and regulates cell proliferation and differentiation. Here, we focus on examining the link between calcium and Ras signalling and, in particular, we speculate as to how the complexity of calcium signalling could regulate Ras activity.
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Acknowledgements
We apologize to colleagues whose original research we could not cite due to space limitations. The work in the laboratory of P.J.C. is supported by grants from the Biotechnology and Biological Sciences Research Council and the Medical Research Council. P.J.L. is a Beit Memorial Research Fellow and P.J.C. is a Lister Institute Research Fellow.
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Department of Biochemistry, The Henry Wellcome Laboratories for Integrated Cell Signalling, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK
Peter J. Cullen & Peter J. Lockyer
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Glossary
- STORE-OPERATED CA2+ CHANNELS
Plasma membrane ion channels, of uncertain identity, that open in response to depletion of internal Ca2+ stores.
- INNER LEAFLET
A lipid layer that faces the inside of the cell.
- PLECKSTRIN HOMOLOGY (PH) DOMAIN
A sequence of 100 amino acids that is present in many signalling molecules and binds to lipid products of phosphatidylinositol metabolism. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.
- IQ MOTIF
A small structural domain that mediates interactions with calmodulin.
- DBL HOMOLOGY (DH) DOMAIN
A sequence that is present in some guanine nucleotide-exchange factors. It was originally identified in the DBL protein, a molecule of unknown function that was found in a human diffuse B-cell lymphoma.
- IONOPHORE
A substance (natural or synthetic, cyclic or linear) that can bind metal ions in solution and transport them across lipid barriers in natural or artificial membranes.
- IONOTROPIC
A type of receptor that mediates its effects by regulating ion channels.
- LONG-TERM POTENTIATION
A long-lasting increase in the efficacy of synaptic transmission, which is commonly elicited by high-frequency neuron stimulation.
- SYNAPTIC PLASTICITY
A change in the functional properties of a synapse as a result of use.
- PANCREATIC β CELL
A cell in the pancreas that manufactures insulin. Destruction of such cells and the consequential lack of insulin lead to type I (insulin-dependent) diabetes mellitus. The disease is believed to be the result of an autoimmune attack on the β-cells.
- DOMINANT-NEGATIVE
A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.
- FIBROBLAST
A common cell type that is found in connective tissue in many parts of the body. This secretes an extracellular matrix that is rich in collagen and other macromolecules, and connects cell layers.
- EF HANDS
Ca2+-binding domains that were originally identified in parvalbumin, and are also known as helix–turn–helix domains.
- C1 DOMAIN
A short, cysteine-rich modular signalling domain of around 50 amino acids. Known to bind diacylglycerol and contribute to the spatio-temporal regulation of proteins such as protein kinase C and GRPs. Some atypical C1 domains have low affinity for diacylglycerol but might be involved in binding proteins, and membrane lipids other than diacylglycerol.
- PRENYLATION
The enzymatic addition of prenyl moieties (geranyl, farnesyl or geranylgeranyl groups) to a protein as a post-translational modification.
- PHORBOL ESTER
A polycyclic ester that is isolated from croton oil. The most common is phorbol myristoyl acetate (PMA, also known as 12,13-tetradecanoyl phorbol acetate or TPA). These are potent co-carcinogens or tumour promoters because they mimic diacylglycerol, and thereby irreversibly activate protein kinase C.
- MYRISTOYLATION
The covalent attachment of a hydrophobic myristoyl group to the amino-terminal glycine residue of a nascent polypeptide.
- PALMITOYLATION
The covalent attachment of a palmitate (16-carbon saturated fatty acid) to a cysteine residue through a thioester bond.
- KERATINOCYTES
Differentiated epithelial cells of the skin.
- C2 DOMAIN
Better known as Ca2+-dependent phospholipid-binding domains in proteins such as conventional protein kinase Cs and synaptotagmin. The C2 domain is another modular signalling domain that can induce membrane–protein, or protein–protein interactions, after binding of several Ca2+ ions. There are C2 domains that do not bind Ca2+ but constitutively bind to a membrane, others that might be involved in Ca2+-independent protein–protein interactions, and some that might bind inositol polyphosphates.
- L-TYPE CA2+ CHANNEL
A form of voltage-operated Ca2+ channel in cardiac muscle that has a high electrical threshold.
- EGTA
Ethylenebis (oxyethylene-trinitrilo) tetraacetic acid. A chelating agent with a high affinity for Ca2+ ions.
- BUFFER LENGTH CONSTANT
This describes the buffering influence that a mobile Ca2+ buffer has on the Ca2+ concentration that emanates from a defined point/source of release or entry, such that the faster the on-rate for Ca2+-binding, the shorter the apparent length constant.
- AEQUORIN
A Ca2+-dependent photoprotein that is responsible for luminescence by oxidation of the chromophore coelenterazine.
- CAMELEON PROTEIN
These are are Ca2+ biosensors that report changes in intracellular Ca2+ over time. The technology is based on two modified green fluorescent proteins at either end of a single peptide that changes conformation when Ca2+ binds, which leads to a detectable change in FRET signal between the different fluorescent protein molecules.
- VOLTAGE-GATED L-TYPE CA2+ CHANNEL
A Ca2+ channel that is sensitive to the voltage difference across the membrane; and is open when voltage reaches critical threshold, level. It is found largely on axon hillocks and the terminals of neurons.
- HYPERVARIABLE DOMAIN
A region immediately upstream of the carboxy terminal CAAX motif of Ras, which is involved in membrane targeting. In the case of K-Ras4B, this comprises a polybasic region of lysine residues.
- THAPSIGARGIN
An inhibitor of endoplasmic reticulum Ca2+-ATPase.
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Cullen, P., Lockyer, P. Integration of calcium and RAS signalling.Nat Rev Mol Cell Biol3, 339–348 (2002). https://doi.org/10.1038/nrm808
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