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American Journal of Clinical Nutrition, Vol. 70, No. 4, 545-556, October 1999
© 1999 American Society for Clinical Nutrition

Report of a Meeting

Receptor-mediated signaling pathways: potential targets of modulation by dietary fatty acids1,2,3,4

Daniel Hwang and Sang H Rhee

1 From the Pennington Biomedical Research Center, Louisiana State University, Baton Rouge.

2 Presented at the workshop Role of Nutrient Regulation of Signal Transduction in Metabolic Diseases organized by the National Institutes of Health Nutrition Study Section.

3 Supported by grants from the USDA (97-35200-4258) and NIH (DK41868).

4 Address reprint requests to D Hwang, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808. E-mail: hwangdh{at}mhs.pbrc.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 TRANSDUCTION OF RECEPTOR...
 RECEPTOR DIMERIZATION OR...
 PROTEIN KINASE CASCADES
 POTENTIAL TARGETS OF MODULATION...
 SUMMARY
 REFERENCES
 
Extracellular signals are transmitted to intracellular targets through many signal-transduction pathways. Each signaling pathway is composed of a network of interacting signaling molecules that regulate diverse cellular responses. A modulation of the functional activities of these signaling molecules as a result of altered nutritional status could lead to qualitative and quantitative changes in cellular responses to extracellular signals. Growing evidence now suggests that fatty acids can directly and indirectly modulate signaling pathways at multiple levels. Elucidating the mechanism of this modulation could help us to understand how different types of dietary fat modify the risks of many chronic diseases.

Key Words: Signal transduction • signaling molecule • fatty acids • dietary fat • tyrosine kinase • protein kinase


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
TRANSDUCTION OF RECEPTOR...
 RECEPTOR DIMERIZATION OR...
 PROTEIN KINASE CASCADES
 POTENTIAL TARGETS OF MODULATION...
 SUMMARY
 REFERENCES
 
Epidemiologic, clinical, and biochemical studies have shown that different types of dietary fatty acids can modify the risks of many chronic diseases, such as cardiovascular diseases, cancer, and inflammatory diseases. However, the molecular and cellular mechanisms by which dietary fatty acids exert such effects are still not well understood. Twenty-carbon polyunsaturated fatty acids such as arachidonic acid (20:4n-6) and eicosapentaenoic acid (20:5n-3) can be enzymatically converted to eicosanoids (1, 2). The revelation that eicosanoids possess diverse pathophysiologic actions as autocrine and paracrine factors has expanded our understanding of the modulatory roles of different fatty acids in various cellular responses, including immune and inflammatory responses (3).

In response to extracellular signals, cells up-regulate or down-regulate the expression of a specific set of genes, leading to altered metabolism, proliferation, differentiation, or apoptosis (Figure 1Go). Elucidating the signal-transduction pathways through which the extracellular signals are transmitted to their intracellular targets is fundamental to understanding the molecular and cellular mechanisms of such cellular responses. Rapidly advancing research in cell signaling pathways has unveiled the possibility that different types of fatty acids can modulate many receptor-mediated signal-transduction pathways. Growing evidence now suggests that fatty acids, in addition to their roles as a structural components of membrane lipids and as precursors of eicosanoids, can act as second messengers or regulators of signal-transducing molecules. Future research on this topic should yield significant new information that will enhance our understanding of the molecular and cellular mechanisms by which different types of dietary fatty acids modify the risks of many chronic diseases. The aims of this review are to briefly overview 1) the basic framework of receptor-mediated signal-transduction pathways, 2) protein kinase cascades, and 3) the potential targets of modulation by dietary fatty acids in these pathways, and to speculate on the nutritional implications of such modulation.



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  		FIGURE 1. Ligand binding of a receptor (R) activates a multitude of downstream signaling pathways, leading to the transcription of a specific set of genes, which in turn leads to diverse cellular responses.

 

   TRANSDUCTION OF RECEPTOR-MEDIATED SIGNALS BY REVERSIBLE PHOSPHORYLATION OF SIGNAL-TRANSDUCING MOLECULES
TOP
 ABSTRACT
 INTRODUCTION
 TRANSDUCTION OF RECEPTOR...
RECEPTOR DIMERIZATION OR...
 PROTEIN KINASE CASCADES
 POTENTIAL TARGETS OF MODULATION...
 SUMMARY
 REFERENCES
 
The general feature of receptor-mediated signal-transduction pathways is that the transmission and amplification of the signals are regulated mostly by reversible protein phosphorylation of signal transducers. Phosphorylation of signaling molecules at specific sites leads to alterations in functional activity, alterations in the localization or binding properties of the molecules, and in some cases to proteolytic degradation. Phosphates are then removed by phosphatases, resulting in reversal of the activation or inactivation. Thus, the length of time the transducers remain active is tightly controlled. Phosphorylation and dephosphorylation (activation or inactivation) of signaling molecules are controlled by kinases and phosphatases as shown in Figure 2Go. Reversible protein phosphorylation is ideally suited for rapid transmission of extracellular signals into the nucleus to induce the expression of a specific set of immediate-early genes without intervening protein synthesis.



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  		FIGURE 2. Ligand binding of a tyrosine kinase receptor induces autophosphorylation of tyrosine kinase residues (Y) of the receptor, resulting in increased receptor kinase activity. The activated receptor kinase can phosphorylate substrates or can be dephosphorylated by phosphatases for inactivation. The coordinated action of kinases and phosphatases is critical for turning signaling pathways "on" or "off."

 
It has been estimated that humans have as many as 2000 protein kinases and 1000 protein phosphatase genes (4, 5). Broadly, there are 2 types of protein kinases: kinases that phosphorylate serine-threonine residues and kinases that phosphorylate tyrosine residues. Phosphotyrosine plays a major role in molecular recognition and in the formation of protein-protein complexes. The Src homology 2 (SH2) domain, which is highly conserved in many signal-transducing molecules, binds to phosphotyrosine (6). The SH2 domain consists of {approx}100 amino acids folded to form a binding pocket for a phosphorylated tyrosine (7). This domain, which is highly conserved in many signal-transducing and adaptor molecules, plays an important role in recruiting or localizing these molecules for functional interactions with other signaling molecules, thereby propagating the signals and gaining specificity. The SH2 domain is also involved in regulating the activation and inactivation of Src kinases by binding phosphorylated tyrosine in a carboxyl terminal regulatory domain (8). The plausible reason for the adoption of tyrosine phosphorylation for intracellular signaling is the successful evolution of high-affinity phosphorylated tyrosine binding domains such as the SH2 domain. Phosphorylated tyrosine may have been selected for this purpose instead of phosphorylated serine or threonine because the aromatic side chain of phosphorylated tyrosine provides a much higher binding energy than those of phosphorylated serine or threonine (4). On the other hand, the main function of phosphoserine and phosphothreonine is to modify the conformation of a molecule to change its functional activity (6). For example, the kinase activity of phosphorylated extracellular-signal-regulated kinase 2 (ERK-2) is 500–1000-fold higher than that of the unphosphorylated enzyme (9). Thus, protein phosphorylation plays critical roles in the transmission, amplification, and specificity of receptor-mediated signals.


   RECEPTOR DIMERIZATION OR OLIGOMERIZATION AND AUTOPHOSPHORYLATION OF GROWTH FACTOR RECEPTORS WITH TYROSINE KINASE ACTIVITY
TOP
 ABSTRACT
 INTRODUCTION
 TRANSDUCTION OF RECEPTOR...
 RECEPTOR DIMERIZATION OR...
PROTEIN KINASE CASCADES
 POTENTIAL TARGETS OF MODULATION...
 SUMMARY
 REFERENCES
 
Most receptor-type kinases identified so far are tyrosine kinases, with the possible exception of transforming growth factor ß receptor, which possesses serine-threonine kinase activity in its cytoplasmic domain. Tyrosine kinase receptors include receptors for platelet-derived growth factor, epidermal growth factor, fibroblast growth factor, and insulin-like growth factor (4, 10). The general steps in a receptor-mediated signaling pathway are depicted in Figure 3Go. The pathway is initiated by dimerization or oligomerization of receptors as a result of binding to their respective ligands. Dimerization or oligomerization is followed by the autophosphorylation of different tyrosine residues in the cytoplasmic domains of receptors possessing intrinsic tyrosine kinase activity (11). Phosphorylation of the tyrosine residues leads to increased kinase activity of the receptor, which in turn stimulates the autophosphorylation of tyrosine residues outside the kinase domain and of tyrosine residues on other signal transducers. Autophosphorylated tyrosine residues outside the kinase domains serve as important docking sites for recruitment of downstream signal transducers containing SH2 domains. The presence of unique epitopes in the cytoplasmic domain of receptors that bind signal transducers containing SH2 domains may confer the specificity of the downstream signaling pathways as depicted in Figure 4Go.



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  		FIGURE 3. General steps in receptor-mediated signaling pathways. SH2 domain, Src homology 2 domain.

 


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  		FIGURE 4. Receptor occupancy by ligands induces autophosphorylation of the cytoplasmic kinase domain, which in turn enhances the phosphorylation of other tyrosine residues (Y). Each phosphorylated tyrosine residue in the context of the surrounding amino acid sequence binds a specific signaling molecule (eg, Src, growth factor receptor–bound protein 2, phosphoinositide-3-kinase, or phospholipase C{gamma}) possessing an Src homology 2 domain, leading to the activation of downstream signaling pathways.

 
Other receptor families such as cytokine receptors, antigen receptors, and tumor necrosis factor receptors lack intrinsic kinase activity in their cytoplasmic domains. Despite the structural differences between these receptors and tyrosine kinase receptors, however, their mechanisms of activation appear to be similar. Many non-receptor-type tyrosine kinases such as Src, focal adhesion kinase, and Janus kinase (JAK) are directly associated with the cytoplasmic domains of receptors lacking kinase activity and act as catalytic subunits of those receptors. For example, the JAK family of non-receptor-type tyrosine kinases is constitutively associated with the intracellular domains of cytokine receptors (12). Ligand-induced receptor oligomerization leads to the activation of JAK, which in turn phosphorylates downstream signal transducers such as STAT (signal transducers and activators of transcription). JAK or other kinases such as Src kinases can also phosphorylate tyrosine residues on the cytokine receptors, creating docking sites for signal transducers containing SH2 domains. This event can initiate signaling pathways similar to those mediated by tyrosine kinase receptors.


   PROTEIN KINASE CASCADES
TOP
 ABSTRACT
 INTRODUCTION
 TRANSDUCTION OF RECEPTOR...
 RECEPTOR DIMERIZATION OR...
 PROTEIN KINASE CASCADES
POTENTIAL TARGETS OF MODULATION...
 SUMMARY
 REFERENCES
 
Protein kinase cascades that transduce diverse receptor-mediated signals include mitogen-activated protein kinase (MAPK), protein kinase C, JAK-STAT, protein kinase A, phosphoinositide 3 kinase (PI-3K), and I{kappa}B{alpha} (inhibitory subunit {alpha}) kinase.

MAPK signal-transduction pathways
MAPK is a conserved signaling module that transduces diverse receptor-mediated signals into a variety of intracellular targets. Currently, 3 distinct MAPK modules are known in vertebrates: ERKs, c-Jun amino terminal kinases, and p38 as shown in Figure 5Go (13–20). Each module consists of 3 protein kinases that act sequentially within one pathway: MEK (MAPK kinase), MEKK (MEK activator), and MAPK. Raf-1, MEK-1, MEK-2, ERK-1, and ERK-2 are the best known vertebrate MAPK modules. The second module consists of MEKK-1 (instead of Raf-1), MKK-4 (the MEK), and stress-activated protein kinase–c-Jun amino terminal kinase. The third module consist of MEKK-1, MKK-3, and p38. The MAPK modules can be activated by receptor tyrosine kinases such as cytokine receptors, antigen receptors, G protein–coupled 7-transmembrane receptors, protein kinase C, and integrins. In addition, various stresses (osmotic stress, ultraviolet light, radiation, and oxidants) directly or indirectly activate MAPK pathways.



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  		FIGURE 5. The mitogen-activated protein kinase (MAPK) cascade. The 3 MAPK modules in mammalian cells are extracellular-signal-regulated kinase (ERK) 1 and 2, c-Jun amino terminal kinase–stress-activated protein kinase (JNK-SAPK), and p38. Briefly, dimerization or oligomerization of growth factor receptors induces autophosphorylation of the tyrosine residues of the cytoplasmic domain, providing the docking site for adaptor molecules containing an Src homology 2 (SH2) domain. Growth factor receptor–bound protein 2 (Grb-2) recruits guanine nucleotide exchange factor (SOS) through its SH3 domain. SOS stimulates GDP-GTP exchange on Ras, which in turn activates downstream kinase cascades. Activated (phosphorylated) MAPKs are translocated into the nucleus, where they phosphorylate (activate) transcription factors. Proximal signaling steps through which stresses activate MAPKs are not well understood. CRE, cAMP response element; MEK or MKK, MAPK kinase; MEKK, MEK kinase; S, serine; SEK, SAPK-ERK kinase; SRE, serum response element; T, threonine; TRE, tetradecanoylphorbol acetate (TPA) response element; UV, ultraviolet light; Y, tyrosine.

 
The MAPK pathways activated by receptor tyrosine kinases are relatively well characterized and are commonly used as a paradigm for receptor-mediated protein kinase cascades. Dimerization or oligomerization and autophosphorylation of tyrosine residues in the cytoplasmic domain provide docking sites for adaptor molecules such as growth factor receptor–bound protein 2. The adaptor molecule recruits guanine nucleotide exchange factor, which has proline-rich SH3 domain binding sites. Guanine nucleotide exchange factor stimulates the exchange of GDP and GTP on Ras. The GTP-bound form of Ras in turn recruits Raf to the membrane, resulting in increased serine-threonine kinase activity of Raf. Raf phosphorylates serine residues and thus activates MEK. MEK is a dual-specificity MAPK that phosphorylates both threonine and tyrosine residues of ERK, resulting in stimulation of the serine-threonine kinase activity of ERK.

Activated ERK translocates into the nucleus and phosphorylates transcription factors such as TCF/Elk-1 and NF-IL6 (14, 21, 22). Activated ERK can also phosphorylate MEK, MEKK-1, and c-Raf-1 (17). This implies that ERK may regulate its own upstream kinases. However, no direct evidence for this hypothesis has been shown. Another group of substrates includes protein kinases located downstream of the MAPK signaling pathway. These include ribosomal S6 kinase, which can increase glycogen synthase phosphatase activity, and MAPK-activated protein kinase 2, which phosphorylates glycogen synthase (14, 17, 23). The epidermal growth factor receptor is also known to be phosphorylated by ERKs (14). However, the functional significance of this is not known. ERKs also phosphorylate cytoplasmic phospholipase A2 (cPLA2) (24, 25). Phosphorylated cPLA2 is translocated to the plasma membrane and catalyzes the release of arachidonic acid from membrane phospholipids. Thus, the phosphorylation of cPLA by MAPK may account for the agonist-stimulated activation of cPLA2 and enhanced production of eicosanoids derived from arachidonic acid.

The 3 MAPK modules are activated with various intensity by the activation of different receptors. Each MAPK module leads to the activation of different sets of transcription factors. Therefore, the types of genes expressed as a result of the activation of MAPK modules depends on the types of agonists and the cell types that define the signaling components. Furthermore, activation of a receptor normally leads to pleiotropic activation of multiple signaling pathways, as shown in Figure 6Go. For example, endotoxin and cytokines can activate not only MAPK modules but also other signaling pathways such as nuclear transcription factor {kappa}B (NF-{kappa}B), ceramide, and JAK-STAT pathways. The pleiotropic activation of multiple signaling pathways and the cooperative nature of transcription factors in activating the transcription machinery make it difficult to predict the entire profile of genes expressed in response to the activation of a particular receptor. Therefore, to understand the mechanism by which activation of a particular receptor leads to final cellular responses (apoptosis, differentiation, or proliferation), we need to identify not only the signaling pathways but also the differentially expressed genes.



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  		FIGURE 6. Pleiotropic activation of signaling pathways by cytokines and endotoxin. CAP, ceramide-activated protein kinase; ERK, extracellular-signal-regulated kinase; I{kappa}B, inhibitory subunit; JAK, Janus kinase; JNK, c-Jun amino terminal kinase; MEK or MKK, mitogen-activated protein kinase (MAPK) kinase; MEKK, MEK kinase; NF-{kappa}B, nuclear transcription factor {kappa}B; SEK, stress-activated protein kinase–ERK kinase; SMase, sphingomyelinase; STAT, signal transducers and activators of transcription.

 
I{kappa}B{alpha} kinase signaling pathway
An alternative strategy for transmitting extracellular signals to the nucleus is the regulation of the nuclear translocation of the transcription factor, as shown for NF-{kappa}B. In unstimulated cells, the different NF-{kappa}B complexes are held in the cytoplasm by interaction with I{kappa}B. After cell stimulation, the NF-{kappa}B–I{kappa}B complex dissociates and NF-{kappa}B dimers are rapidly translocated to the nucleus (22). This dissociation is achieved by inducible proteolytic degradation of I{kappa}B, which requires prior phosphorylation by I{kappa}B{alpha} kinase (26), as depicted in Figure 7Go. Many extracellular signals capable of activating the NF-{kappa}B pathway have been identified. However, the upstream signaling pathways leading to the activation of I{kappa}B{alpha} kinase are not well understood. Recently, an NF-{kappa}B-inducing kinase was identified and shown to be related to MEKK and to activate I{kappa}B (27). A constitutively active form of MEKK-1 that activates c-Jun amino terminal kinase was also shown to activate I{kappa}B kinase (28). However, whether MEKK-1 is a physiologic upstream kinase that activates I{kappa}B kinase is not clear. The expression of many immediate-early genes such as cytokines, inducible nitric oxide synthase, cyclooxygenase, and growth factor genes is known to be induced by the activation of NF-{kappa}B (29–32).



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  		FIGURE 7. Hypothetical signaling pathways mediated by ceramide. Receptor activation induces the activation of neutral sphingomyelinase (SMase) by unknown mechanisms. This leads to the hydrolysis of sphingomyelin (SM) and the generation of ceramide, which in turn activates various downstream signaling pathways. cPLA2, cytosolic phospholipase A2; I{kappa}B, inhibitory subunit; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; NF-{kappa}B, nuclear transcription factor {kappa}B; NIK, NF-{kappa}B–inducing kinase.

 
Sphingomyelin signaling pathways
A growing number of cell surface receptors are known to generate signals that stimulate the hydrolysis of sphingomyelin to release ceramide. These receptors include cytokine receptors, tumor necrosis factor receptors, endotoxin receptor (CD14), and nerve growth factor receptor (33, 34). In addition, stresses such as nutrient withdrawal and irradiation stimulate the generation of ceramide from sphingomyelin. Accumulated evidence now suggests that ceramide is one of the key second messengers derived from membrane phospholipids. Results from studies performed by using cell-permeable ceramide showed that ceramide activates various serine-threonine kinases, including MAPK, and also activates ceramide-activated protein phosphatase, NF-{kappa}B, and cPLA2 (33–36) as depicted in Figure 7Go. The presence of 2 types of sphingomyelinases has been shown; each sphingomyelinase acts on substrates from different cellular compartments. This suggests that each sphingomyelinase is coupled to different upstream signaling components (34). Biological effects of ceramide include differentiation, apoptosis, and proliferation. These effects vary with cell types (36, 37). The upstream signaling events that lead to the activation of sphingomyelinase and downstream signaling pathways leading to ceramide-induced cellular responses are still largely unknown.

JAK-STAT pathway
Cytokines such as interleukin 2 (IL-2), IL-3, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor, interferon {alpha}, interferon ß, interferon {gamma}, and growth factors such as growth hormone and erythropoietin function through members of the cytokine receptor superfamily (38). The long form of the leptin receptor also belongs to this cytokine receptor superfamily (39, 40). Unlike those of tyrosine kinase receptors, the intracellular domains of cytokine receptors lack intrinsic kinase activity. However, as non-receptor-type tyrosine kinases, JAKs are constitutively associated with the cytoplasmic domains of cytokine receptors. Dimerization or oligomerization of cytokine receptors induced by ligand binding leads to the activation of JAKs, which in turn phosphorylate tyrosine residues on cytokine receptors. Phosphorylated tyrosines serve as the docking sites for signaling molecules possessing SH2 domains. Activated JAKs phosphorylate latent cytoplasmic transcription factors, such as STATs (12, 41). Tyrosine-phosphorylated STATs dimerize through juxtaposed SH2 domains, translocate into the nucleus, and activate cytokine-inducible genes (22).

PI-3K pathway
The important role that membrane phospholipids play in signaling processes began to be recognized when inositol 1,4,5-trisphosphate and diacylglycerol, the hydrolysis products of phosphatidylinositol 4,5-bisphosphate by phospholipase C, were found to regulate intracellular Ca2+ and protein kinase C, respectively (42). These phosphoinositides are also substrates for PI-3Ks, which phosphorylate the hydroxyl group at position 3 on the inositol ring (43). The 3-phosphoinositides derived from the actions of a family of PI-3Ks appear to regulate multiple cell functions such as cell adhesion, chemotaxis, apoptosis, secretory responses, insulin-mediated membrane translocation of glucose transporters, platelet activation, and cytoskeletal reorganization (44). PI-3Ks catalyze the phosphorylation of phosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3-phosphate, phosphatidylinositol 3,4-bisphosphate, and phosphatidylinositol 3,4,5-trisphosphate, respectively. Phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate are almost absent in resting cells. However, their intracellular concentrations increase sharply on stimulation with a variety of ligands, suggesting that they function as second messengers (43). Ligands known to stimulate PI-3Ks include growth factors, non-receptor-type oncogenes, and cytokines (45). The SH2 domain of PI-3Ks can interact directly with phosphorylated tyrosine residues of receptor tyrosine kinases.

The protein targets of 3-phosphoinositides identified so far include certain protein kinase C isoforms and protooncogenic protein kinase (PKB), which contains the Pleckstrin homology domain (44, 46, 47). The Pleckstrin homology domain of PKB is the binding site of 3-phosphoinositides. Thus, ligand-induced activation of growth factor receptors leads to recruitment and activation of PI-3Ks, resulting in the stimulation of phosphatidylinositol 3,4,5-trisphosphate synthesis. Phosphatidylinositol 3,4,5-trisphosphate in turn activates phosphoinositide-dependent protein kinase and binds to the Pleckstrin homology domain of PKB. The phosphorylation of PKB by phosphoinositide-dependent protein kinases and binding of the Pleckstrin homology domain of PKB by phosphatidylinositol 3,4,5-trisphosphate lead to the activation of PKB and trigger PKB-dependent cellular responses (Figure 8Go). Several other signaling molecules containing the Pleckstrin homology domain have been identified (44) and it is now thought that Pleckstrin homology domains function as signal-dependent membrane adaptors.



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  		FIGURE 8. Potential targets that can be modulated by dietary fatty acids in receptor-mediated signaling pathways. CAP, ceramide-activated protein kinase; cPLA2, cytosolic phospholipase A2; DAG, diacylglycerol; FA, fatty acid; I{kappa}B, inhibitory subunit; PDK, phosphoinositide-dependent protein kinase; PKA, cAMP-dependent protein kinase; PKB, protooncogenic protein kinase; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol trisphosphate; PLC, phospholipase C; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; PPAR, peroxisome proliferator-activated receptor; SMase, sphingomyelinase.

 
Cyclic AMP–dependent protein kinase
Various growth factors induce mitogenesis through the activation of receptor-coupled specific heterotrimeric G proteins by the binding of GTP and the release of the {alpha} subunit from the complex (48, 49). The {alpha} subunit–GTP complex activates adenylate cyclase. Cyclic AMP (cAMP) is liberated from the intracellular face of the plasma membrane and then activates cAMP-dependent protein kinase (PKA) (Figure 8Go). PKA enhances or initiates cell proliferation in several cell types (48, 49) and stimulates or inhibits the transcription of specific genes through a cAMP-responsive element (48–50). This element is activated by cAMP-responsive-element binding protein, which requires phosphorylation by PKA.

Recently, a family of cAMP binding proteins that directly activates the Ras superfamily guanine nucleotide binding protein in a cAMP-dependent but PKA-independent manner have been identified (51). These cAMP binding proteins may have other target molecules that mediate diverse cellular responses. This finding suggests the need to revise the concept of cAMP-mediated signaling pathways.

Protein kinase C
Protein kinase C enzymes (PKCs) transduce a variety of signals mediated by the phospholipid hydrolysis that results from the activation of various receptors. Activation of G protein–coupled receptors, tyrosine kinase receptors, and non-receptor-type tyrosine kinases can activate phospholipase C. Phospholipase C hydrolyzes phosphatidylinositol 4,5-bisphosphate to yield diacylglycerol and inositol 1,4,5-trisphosphate (52, 53) (Figure 8Go). Diacylglycerol activates PKCs by binding to their regulatory domains (54). Inositol 1,4,5-trisphosphate increases intracellular Ca2+, which in turn stimulates the activation of PKCs. PKC activation is known to be involved in diverse array of cellular responses in endocrine, exocrine, nervous, muscular, inflammatory, and immune systems (52, 53). Despite the broad substrate specificity of many proteins tested in vitro on serine and threonine residues, but not tyrosine residues, the nature of the physiologic substrates of PKCs is still not clearly understood.


   POTENTIAL TARGETS OF MODULATION BY DIETARY FATTY ACIDS IN RECEPTOR-MEDIATED SIGNALING PATHWAYS
TOP
 ABSTRACT
 INTRODUCTION
 TRANSDUCTION OF RECEPTOR...
 RECEPTOR DIMERIZATION OR...
 PROTEIN KINASE CASCADES
 POTENTIAL TARGETS OF MODULATION...
SUMMARY
 REFERENCES
 
Signaling molecules that may be modulated by different fatty acids can be divided into 3 groups (Figure 9Go).



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  		FIGURE 9. Targets that can be modulated by dietary fatty acids in receptor-mediated signaling pathways are divided into 3 groups. DAG, diacylglycerol; FA, fatty acid; PIP3, phosphatidylinositol trisphosphate; PKC, protein kinase C; PLC, phospholipase C; PPAR, peroxisome proliferator-activated receptor.

 
Signaling molecules that require fatty acid acylation for membrane translocation and functional activation
Many signaling molecules are highly compartmentalized. Activation of receptors by ligand binding leads to the translocation of signaling molecules that can interact with receptors or other downstream signaling molecules to initiate signal propagation. This translocation can be achieved by binding between molecular binding domains such as SH2 or SH3 and their docking sites (phosphorylated tyrosine or proline-rich regions for SH2 and SH3, respectively) on counterpart molecules. In other cases (eg, PKA), specific anchoring proteins fulfill such translocation functions. Evidence accumulated recently indicates that long-chain fatty acids can be covalently attached to a variety of proteins and can dramatically influence translocation and protein function (55, 56). Many molecules that play critical roles in transmitting extracellular signals are known to be acylated for their membrane translocation. Two modes of acylation for these molecules have been described. These are cotranslational myristoylation and posttranslational palmitoylation.

Amino terminal myristoylation
Myristoylation occurs cotranslationally at amino terminal glycine residues through covalent amide bond formation (57). Myristoylated proteins contain a consensus sequence of Met-Gly-Xaa-Xaa-Xaa-Ser/Thr (where Xaa is an unspecified amino acid; 58). The half-life of the myristoyl moiety is known to be equivalent to that of the polypeptide backbone, indicating that myristoylation is a permanent modification (58). The signaling molecules known to be myristoylated include GTP-binding proteins ({alpha}), cAMP-dependent protein kinase, and members of the Src family of non-receptor-type tyrosine kinases (55, 56). Myristoylation can increase the hydrophobicity of proteins and thus facilitate membrane anchorage. However, it has been suggested that myristoylation alone is not sufficient for stably anchoring a myristoylated protein to the lipid bilayer (59). Additional factors may be required to promote the membrane localization of myristoylated proteins. The enzyme catalyzing the myristoylation of the glycine residue is considered to have a high degree of substrate specificity for myristoyl-CoA (55). However, analyses of the acylation of bovine retinal transducin and recoverin revealed that acyl moieties [eg, 12:0, 14:1(5), and 14:2(5,8)] other than 14:0 can be covalently bound to the amino terminal glycine residue (60, 61). It has also been shown that other acyl-CoAs significantly inhibit binding of [14C]myristoyl-CoA to the enzyme (62). In vitro studies of a partially purified myristoyl-CoA synthase activity recovered from a human erythroleukemia cell line indicated that the enzyme can catalyze acylation with 12:0 as well as with 14-carbon fatty acids with double bonds (63). These observations suggest that acylation of amino terminal glycine can be regulated by the availability of alternative acyl chains. This in turn leads to the important question of whether dietary fatty acids can modulate myristoylation of signaling proteins. The facts that myristoylation is a cotranslational event and that the half-life of the myristoyl moiety is the same as the protein itself indicate that myristoylation is not a reversible process. Thus, myristoylation is not likely to be dynamically regulated as in the case of reversible palmitoylation.

Palmitoylation
In palmitoylation, palmitate is attached posttranslationally to cysteine residues via a labile thioester linkage. Palmitoylation is a reversible process that is dynamically regulated. Biophysical measurement suggests that myristoylation provides barely enough binding energy to associate a protein with membrane lipids (59). The greater hydrophobicity of thioester-linked palmitate can enhance the membrane association of the proteins (58). The roles for fatty acid acylation of proteins include anchoring proteins to membranes (64), stabilizing protein-protein interactions, and regulating enzymatic activities in mitochondria (64). Mutations that prevent fatty acid acylation abolish or attenuate the biological function of these proteins. Palmitoylated proteins can be categorized into 3 groups (65). The first group includes transmembrane proteins that are acylated at cysteine residues. The second group includes the Ras family, in which palmitoylation occurs in the carboxyl terminal region and requires prior isoprenylation of the cysteine residue in the CAAX box (66, 67). The third group includes the {alpha} subunits of GTP-binding proteins and Src family tyrosine kinases (65). This group of proteins is both myristoylated and palmitoylated. A comprehensive list of acylated proteins is reviewed elsewhere (56). Palmitoylation of G proteins, Ras, and Src family tyrosine kinases is of particular interest because these proteins are proximal components that transduce diverse receptor-mediated signals (Figures 8 and 9GoGo). The reversibility of palmitoylation implies that these proteins are the logical targets of modulation by dietary fatty acids.

In contrast with myristoylation, the enzymology of palmitoylation is not well characterized. Several questions have immense nutritional implications. One question is whether fatty acids other than palmitate can acylate the cysteine residues, and if so, whether this affects the functional properties of the proteins. Competition assays for G protein palmitoyl-transferase with various unlabeled acyl-CoAs indicate that palmitate is a preferred substrate for the enzyme (68). However, other acyl-CoAs also significantly inhibit palmitoyl-transferase activity, implying that other fatty acids can either be substrates for the acylation of cysteine residues or can inhibit palmitoylation. This leads to the possibility that dietary fatty acids can modulate fatty acid acylation of the signaling molecules. Because G proteins and Ras and Src family tyrosine kinases are proximal components in diverse receptor-mediated signaling pathways, modulation of their functional activity by dietary fatty acids may affect downstream signaling pathways and target gene expression.

Lipid mediators containing different fatty acids or free fatty acids
PI-3K–derived products
PI-3Ks phosphorylate various phosphoinositides (43). Phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate activate PKB (Figure 8Go; 43, 44), which participates in the activation of the ribosomal protein S6 kinase (69), inhibits glycogen synthase kinase 3, and inhibits apoptotic cell responses (70). Results from a recent study indicate that the activity of phosphatidylinositol 3,4,5-trisphosphate varies with the types of fatty acids in the sn-1 and sn-2 positions (46). Because the composition of the fatty acids in the sn-1 and sn-2 positions of phosphoinositides can be altered by dietary fatty acids, it is possible that dietary fatty acids modulate the activities of PKB and its downstream substrates.

Ceramide
Ceramide released from the hydrolysis of sphingomyelin contains one fatty acyl moiety linked to the sphingosine backbone by an amide bond. Whether the type of this fatty acyl moiety can be altered by different fatty acids is not known. The structure-activity relation of ceramide containing different fatty acyl moieties has also not been determined. In most in vitro studies reported, water-soluble ceramides with short-chain fatty acyl groups were used. Ceramide has emerged as an intracellular signal effector molecule with multiple downstream targets for diverse extracellular signals. Modulation of the activity of ceramide by dietary fatty acids would have profound nutritional implications.

Diacylglycerol
Because the fatty acid composition of membrane phospholipids is modified by different dietary fatty acids, fatty acyl moieties of diacylglycerol should also be altered by dietary fatty acids. An alkyl group instead of an acyl group in the 1-ester bond diminishes the activity of diacylglycerol in activating PKC (71). Cho and Ziboh (72) showed that diacylglycerol containing 13-hydroxyoctadecadienoic acid, a 15-lipoxygenase metabolite of linoleic acid, at the 2-position inhibits PKC-ß isozymes in contrast with 1,2-dioleoylglycerol. However, the structure-activity relation for the different acyl groups in the 1- and 2-ester bonds of diacylglycerol is largely unknown.

Fatty acids
In mammalian cells, most long-chain fatty acids are esterified in cellular lipids. Thus, the concentrations of unesterified fatty acids are generally low. However, fatty acids are rapidly released by the activation of various phospholipase A2 and monoacylglycerol and diacylglycerol lipases in response to diverse cellular stimulations (Figure 8Go). Cytosolic phospholipase A2, which is activated by phosphorylation by MAPKs (73, 74), has a high degree of substrate specificity for arachidonic acid in the sn-2 position of phospholipids. Arachidonic acid can be metabolized via cyclooxygenase and lipoxygenase pathways. Cyclooxygenase-derived products of arachidonic acid such as prostanoids can activate their receptors, which are known to be G protein–coupled 7-transmembrane receptors, in a paracrine fashion. There are 2 major branches of prostanoid receptors: one group that activates adenylate cyclase and a second group that either stimulates phosphatidylinositol hydrolysis or inhibits adenylate cyclase (75). It has been well documented that dietary fatty acids can modulate the biosynthesis of prostanoids by altering the availability of the substrate, arachidonic acid. This suggests that dietary fatty acids can regulate prostanoid receptor-mediated signaling pathways.

Signaling molecules that can be modulated by different fatty acids
It was shown that various polyunsaturated fatty acids and prostanoids are the ligands for peroxisome proliferator-activated receptor, a nuclear hormone receptor that regulates the transcription of genes involved not only in lipid metabolism but also in diverse cellular responses (76–79). cis-Unsaturated fatty acids including oleic, linoleic, linolenic, arachidonic, and docosahexaenoic acids enhance the activation of PKCs by diacylglycerol (80). Unsaturated fatty acids also enhance the activation of phospholipase C{gamma} in the presence of Tau proteins (81). Of the unsaturated fatty acids tested, arachidonic acid was the most potent stimulator of phospholipase C{gamma}. However, no apparent difference in potency was observed among the unsaturated fatty acids tested in activating PKCs. In addition, it was shown that arachidonic acid and other fatty acids regulate the activities of multiple cellular proteins, including ion channels and protein kinases (82).


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 TRANSDUCTION OF RECEPTOR...
 RECEPTOR DIMERIZATION OR...
 PROTEIN KINASE CASCADES
 POTENTIAL TARGETS OF MODULATION...
 SUMMARY
REFERENCES
 
The composition of the fatty acids released from membrane phospholipids when cells are stimulated is modified by the composition of dietary fatty acids. Thus, it can be inferred that signaling pathways modulated by fatty acids are in turn modulated by dietary fatty acids. Accumulated evidence, as discussed in this review, suggests that dietary fatty acids can regulate signaling pathways at multiple levels: through cell surface receptors (eg, prostaglandin receptors), through proximal components of receptor-mediated signaling pathways (eg, G proteins and Ras and Src family kinases), at intermediate signaling steps (eg, phospholipase C and PKCs), and through nuclear receptors (eg, peroxisome proliferator-activated receptor). A simplified summary of this modulation is depicted in Figures 8 and 9GoGo. It would be a challenging task to quantitatively determine how changes in the composition of fatty acids in tissue lipids affect the many signaling pathways and final cellular responses. Such a task will require innovative experimental approaches and application of state-of-the-art cellular and molecular biology techniques in well-defined in vivo and in vitro experimental models. Increased research in this area in coming decades will undoubtedly yield significant new information that will help us understand the molecular and cellular mechanisms by which dietary fatty acids modify the risks of many chronic diseases.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 TRANSDUCTION OF RECEPTOR...
 RECEPTOR DIMERIZATION OR...
 PROTEIN KINASE CASCADES
 POTENTIAL TARGETS OF MODULATION...
 SUMMARY
 REFERENCES
 

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Received for publication October 30, 1998. Accepted for publication March 4, 1999.




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