Baumann, C. A. and Saltiel, A. R. (2001). Spatial compartmentalization of signal transduction in insulin action. Bioessays 23(3): 215-222. Direct link - Acrobat reader required
Czech, M. P. and Corvera, S. (1999). Signaling Mechanisms That Regulate Glucose Transport. J. Biol. Chem. 274: 1865-1868. Direct link
Kapeller, R., et al. (1999). Tyrosine phosphorylation of tub and its association with Src homology 2 domain-containing proteins implicate tub in intracellular signaling by insulin. J. Biol. Chem. 274(35): 24980-6. Direct link
Kimura, K. D., et al. (1997). daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277(5328): 942-6. Direct link
Rutter, G. A. (2000). Diabetes: the importance of the liver. Curr Biol. 10(20): R736-8. Direct link
Tissenbaum, H. A. and Ruvkun, G. (1998). An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Genetics 148(2): 703-17. Direct link
Woods, S. C., et al. (1998). Signals that regulate food intake and energy homeostasis. Science 280: 1378-1383. Direct link
In mammals, insulin signalling regulates glucose transport together with the expression and activity of various metabolic enzymes. In the nematode Caenorhabditis elegans, a related pathway regulates metabolism, development and longevity. Wild-type animals enter the developmentally arrested dauer stage in response to high levels of a secreted pheromone, accumulating large amounts of fat in their intestines and hypodermis. Mutants in DAF-2 (a homolog of the mammalian insulin receptor) and AGE-1 (a homolog of the catalytic subunit of mammalian phosphatidylinositol 3-OH kinase) arrest development at the dauer stage. Moreover, animals bearing weak or temperature-sensitive mutations in daf-2 and age-1 can develop reproductively, but nevertheless show increased energy storage and longevity. Null mutations in daf-16 (Drosophila homolog: foxo coding for a forkhead family transcription factor target of the insulin signaling pathway) suppress the effects of mutations in daf-2 or age-1; lack of daf-16 bypasses the need for this insulin receptor-like signalling pathway. The principal role of DAF-2/AGE-1 signalling is thus to antagonize DAF-16. daf-16 is widely expressed and encodes three members of the Fork head family of transcription factors. The DAF-2 pathway acts synergistically with the pathway activated by a nematode TGF-beta-type signal, DAF-7, suggesting that DAF-16 cooperates with nematode SMAD proteins in regulating the transcription of key metabolic and developmental control genes. The probable human orthologs of DAF-16, FKHR and AFX, may also act downstream of insulin signalling and cooperate with TGF-beta effectors in mediating metabolic regulation. These genes may be dysregulated in diabetes (Ogg, 1997).
The wild-type Caenorhabditis elegans nematode ages rapidly, undergoing development, senescence, and death in less than 3 weeks. In contrast, mutants with reduced activity of the gene daf-2, a homolog of the insulin and insulin-like growth factor receptors, age more slowly than normal and live more than twice as long. These mutants are active and fully fertile and have normal metabolic rates. The life-span extension caused by daf-2 mutations requires the activity of the gene daf-16. daf-16 appears to play a unique role in life-span regulation and encodes a member of the hepatocyte nuclear factor 3 (HNF-3)/forkhead family of transcriptional regulators. In humans, insulin down-regulates the expression of certain genes by antagonizing the activity of HNF-3, raising the possibility that aspects of this regulatory system have been conserved (Lin, 1997).
In C. elegans, mutations that reduce the activity of an insulin-like receptor (daf-2) or a phosphatidylinositol-3-OH kinase (age-1) favor entry into the dauer state during larval development and extend lifespan in adults. Downregulation of this pathway activates a forkhead transcription factor (daf-16), which may regulate targets that promote dauer formation in larvae and stress resistance and longevity in adults. In yeast, the SIR2 gene determines the lifespan of mother cells, and adding an extra copy of SIR2 extends lifespan. Sir2 mediates chromatin silencing through a histone deacetylase activity that depends on NAD (nicotinamide adenine dinucleotide) as a cofactor. A survey was performed of the lifespan of C. elegans strains containing duplications of chromosomal regions. A duplication containing sir-2.1-the C. elegans gene most homologous to yeast SIR2-confers a lifespan that is extended by up to 50%. Genetic analysis indicates that the sir-2.1 transgene functions upstream of daf-16 in the insulin-like signalling pathway. These findings suggest that Sir2 proteins may couple longevity to nutrient availability in many eukaryotic organisms (Tissenbaum, 2001).
The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Mutants in this pathway remain youthful and active much longer than normal animals and can live more than twice as long. This lifespan extension requires DAF-16, a forkhead/winged-helix transcription factor. DAF-16 is thought to be the main target of the DAF-2 pathway. Insulin/IGF-1 signaling is thought to lead to phosphorylation of DAF-16 by AKT activity, which in turn shortens lifespan. The DAF-2 pathway prevents DAF-16 accumulation in nuclei. Disrupting Akt-consensus phosphorylation sites in DAF-16 causes nuclear accumulation in wild-type animals, but, surprisingly, has little effect on lifespan. Thus the DAF-2 pathway must have additional outputs. Lifespan in C. elegans can be extended by perturbing sensory neurons or germ cells. In both cases, lifespan extension requires DAF-16. Both sensory neurons and germline activity regulate DAF-16 accumulation in nuclei, but the nuclear localization patterns are different. Together these findings reveal unexpected complexity in the DAF-16-dependent pathways that regulate aging (Lin, 2001).
Aging and limited life span are fundamental biological phenomena observed in a variety of species. Approximately 55 genes have been identified that can extend longevity when altered in Caenorhabditis elegans. These genes include an insulin-like receptor (daf-2) and a phosphatidylinositol 3-OH kinase (age-1) regulating a forkhead transcription factor (daf-16), as well as genes mediating metabolic throughput, sensory perception, and reproduction. Moreover, these mutant alleles both extend life span and increase resistance to ultraviolet (UV) radiation, heat, and oxidative stress, though the stress resistance of clk-1 is controversial. With the exception of old-1 and perhaps some other genes, all of the life-extension alleles are hypomorphic or nullomorphic. OLD-1 transmembrane tyrosine kinase (formerly TKR-1) is expressed in a variety of tissues, is stress inducible, and is a positive regulator of longevity and stress resistance. The transcription of old-1 is upregulated in long-lived age-1 and daf-2 mutants and is upregulated in response to heat, UV light, and starvation. Both RT-PCR and analysis of an OLD-1::GFP tag suggest that old-1 expression is dependent on daf-16. Importantly, old-1 is required for the life extension of age-1 and daf-2 mutants. This study reveals a new system for specifying longevity and stress resistance and suggests possible mechanisms for mediating life extension by dietary restriction and hormesis (Murakami, 2001).
The daf-2 insulin-like receptor pathway regulates development and life-span in Caenorhabditis elegans. Reduced DAF-2 signaling leads to changes in downstream targets via the daf-16 gene, a fork-head transcription factor that is regulated by DAF-2, and results in extended life-span. This study describes the first identification of genes whose expression is controlled by the DAF-2 signaling cascade. dao-1, dao-2, dao-3, dao-4, dao-8 and dao-9 are down-regulated in daf-2 mutant adults compared to wild-type adults, whereas dao-5, dao-6 and dao-7 are up-regulated. The latter genes are negatively regulated by DAF-2 signaling and positively regulated by DAF-16. Positive regulation by DAF-2 of dao-1, dao-4 and dao-8 is mediated by DAF-16, whereas daf-16 mediates only part of DAF-2 signaling for dao-2 and dao-9. Regulation by DAF-2 is most likely DAF-16 independent for dao-3 and hsp-90. RNA levels of dao-5 and dao-6 show elevated expression in daf-2 adults, as well as being strongly expressed in dauer larvae. In contrast, hsp-90 transcript levels are low in daf-2 mutant adults though they are enriched in dauer larvae, indicating overlapping but not identical mechanisms of efficient life maintenance in stress-resistant dauer larvae and long-lived daf-2 mutant adults. dao-1, dao-8 and dao-9 are homologs of the FK506 binding proteins that interact with the mammalian insulin pathway. dao-3 encodes a putative methylenetetrahydrofolate dehydrogenase. DAO-5 shows 33% identity with human nucleolar phosphoprotein P130. dao-7 is similar to the mammalian ZFP36 protein. Distinct regulatory patterns of dao genes implicate their diverse positions within the signaling network of DAF-2 pathway, and suggest they have unique contributions to development, metabolism and longevity (Yu, 2001).
C. elegans insulin-like signaling regulates metabolism, development, and life span. This signaling pathway negatively regulates the activity of the forkhead transcription factor DAF-16. daf-16 encodes multiple isoforms that are expressed in distinct tissue types and are probable orthologs of human FKHRL1, FKHR, and AFX. Human FKHRL1 can partially replace DAF-16, proving the orthology. In mammalian cells, insulin and insulin-like growth factor signaling activate AKT/PKB kinase to negatively regulate the nuclear localization of DAF-16 homologs. The absence of AKT consensus sites on DAF-16 is sufficient to cause dauer arrest in daf-2 plus animals, proving that daf-16 is the major output of insulin signaling in C. elegans. FKHR, FKRHL1, and AFX may similarly be the major outputs of mammalian insulin signaling. daf-2 insulin signaling, via AKT kinases, negatively regulates DAF-16 by controlling its nuclear localization. Surprisingly, daf-7 TGF-beta signaling also regulates DAF-16 nuclear localization specifically at the time when the animal makes the commitment between diapause and reproductive development. daf-16 function is supported by the combined action of two distinct promoter/enhancer elements, whereas the coding sequences of two major DAF-16 isoforms are interchangeable. Together, these observations suggest that the combined effects of transcriptional and posttranslational regulation of daf-16 transduce insulin-like signals in C. elegans and perhaps more generally (Lee, 2001).
Signaling from the DAF-2/insulin receptor to the DAF-16/FOXO transcription factor controls longevity, metabolism, and development in disparate phyla. To identify genes that mediate the conserved biological outputs of daf-2/insulin-like signaling, comparative genomics were used to identify 17 orthologous genes from Caenorhabditis and Drosophila, each of which bears a DAF-16 binding site in the promoter region. One-third of these DAF-16 downstream candidate genes are regulated by daf-2/insulin-like signaling in C. elegans, and RNA interference inactivation of the candidates show that many of these genes mediate distinct aspects of daf-16 function, including longevity, metabolism, and development (Lee, 2003).
let-502 rho-binding kinase and mel-11 myosin phosphatase regulate Caenorhabditis elegans embryonic morphogenesis. Genetic analysis presented here establishes the following modes of let-502 action: (1) loss of only maternal let-502 results in abnormal early cleavages, (2) loss of both zygotic and maternal let-502 causes elongation defects, and (3) loss of only zygotic let-502 results in sterility. The morphogenetic function of let-502 and mel-11 is apparently redundant with another pathway since elimination of these two genes results in progeny that undergo near-normal elongation. Triple mutant analysis indicates that unc-73 (Rho/Rac guanine exchange factor) and mlc-4 (myosin light chain) act in parallel to or downstream of let-502/mel-11. In contrast mig-2 (Rho/Rac), daf-2 (insulin receptor), and age-1 (PI3 kinase) act within the let-502/mel-11 pathway. Mutations in the sex-determination gene fem-2, which encodes a PP2c phosphatase (unrelated to the MEL-11 phosphatase), enhances mutations of let-502 and suppressed those of mel-11. fem-2's elongation function appears to be independent of its role in sexual identity since the sex-determination genes fem-1, fem-3, tra-1, and tra-3 have no effect on mel-11 or let-502. By itself, fem-2 affects morphogenesis with low penetrance. fem-2 blocks the near-normal elongation of let-502; mel-11, indicating that fem-2 acts in a parallel elongation pathway. The action of two redundant pathways likely ensures accurate elongation of the C. elegans embryo (Piekny, 2002).
In Caenorhabditis elegans, an insulin-like signaling pathway, which includes the daf-2 and age-1 genes, controls longevity and stress resistance. Downregulation of this pathway activates the forkhead transcription factor DAF-16, whose transcriptional targets are suggested to play an essential role in controlling the phenotypes governed by this pathway. The genes that have the DAF-16 consensus binding element (DBE) within putative regulatory regions have been surveyed. One such gene, termed scl-1, is a positive regulator of longevity and stress resistance. Expression of scl-1 is upregulated in long-lived daf-2 and age-1 mutants and is undetectable in a short-lived daf-16 mutant. SCL-1 is a putative secretory protein with an SCP domain and is homologous to the mammalian cysteine-rich secretory protein (CRISP) family. scl-1 is required for the extension of the life span of daf-2 and age-1 mutants, and downregulation of scl-1 reduces both life span and stress resistance of this animal. SCL-1, whose expression is dependent on DAF-16, is the first example of a putative secretory protein that positively regulates longevity and stress resistance (Ookuma, 2003).
The life span of C. elegans is extended by mutations that inhibit the function of sensory neurons. In this study, specific subsets of sensory neurons are shown to influence longevity. Certain gustatory neurons inhibit longevity, whereas others promote longevity, most likely by influencing insulin/IGF-1 signaling. Olfactory neurons also influence life span, and they act in a distinct pathway that involves the reproductive system. In addition, a putative chemosensory G protein-coupled receptor expressed in some of these sensory neurons inhibits longevity. Together these findings imply that the life span of C. elegans is regulated by environmental cues and that these cues are perceived and integrated in a complex and sophisticated fashion by specific chemosensory neurons (Alcedo, 2004).
These findings suggest that gustatory neurons are likely to influence life span by perturbing the insulin/IGF-1 pathway. One possibility is that these neurons sense cues that regulate the release of insulin/IGF-1-like hormones that influence the insulin/IGF-1 receptor DAF-2 activity. The C. elegans genome contains more than 30 insulin/IGF-1 homologs, and several of these are expressed in gustatory neurons. The model is favored that longevity-inhibiting ASI and ASG neurons exert their effects on life span by inhibiting the activities of the ASJ and ASK neurons. Thus, one possibility is that the ASI and ASG neurons prevent the longevity-promoting ASJ and ASK neurons from producing a DAF-2 antagonist. It is intriguing that double mutants that have defects in proteins thought to be required for neuronal insulin secretion and in daf-2 activity have an intermediate life span between those of the corresponding neurosecretory single mutants and daf-2 hypomorphic single mutants. This finding is consistent with the idea that some sensory neurons might secrete DAF-2 antagonists (Alcedo, 2004).
A number of insulin-like peptides have now been implicated in the regulation of aging. One such candidate DAF-2 antagonist is ins-1, but this gene is expressed not only in longevity-promoting neurons but also in longevity-inhibiting neurons. At this point, the information available about specific insulin-like peptides does not suggest simple models that explain the data. However, this may change as more is learned about the functions of these proteins. For example, it is possible that other insulin/IGF-1-like peptides function as antagonists in the ASJ and ASK neurons but not in the ASI and ASG neurons, since other insulin/IGF-1-like peptides are expressed in ASJ (Alcedo, 2004).
These observations suggest that olfactory neurons act in a regulatory pathway distinct from gustatory neurons to affect life span. (1) The combined ablation of the gustatory ASI and olfactory AWA and AWC neurons increases life span more than does ablation of either ASI or of AWA and AWC neurons alone. (2) Killing ASJ and ASK suppresses the longevity of ASI-ablated animals but not that of olfactory neuron-ablated animals. (3) The life span extension produced by killing gustatory neurons is completely daf-16 dependent, whereas the life span extension produced by killing olfactory neurons is only partially daf-16 dependent (Alcedo, 2004).
Olfactory neurons may influence life span by perturbing an endocrine signaling pathway that involves the reproductive system. Previous findings have suggested that the germline of C. elegans generates a signal that inhibits longevity and is counterbalanced by a signal from the somatic gonad that promotes longevity. Like the olfactory neurons characterized, the somatic gonad of C. elegans affects life span, at least in part, in a daf-16-independent fashion. In addition, olfactory neurons are required for the somatic gonad to influence life span. In wild-type animals, killing the somatic gonad precursors completely prevents germline ablation from extending life span, but in animals lacking olfactory neurons, it does not. One possibility is that olfactory neurons regulate the release of a hormone that allows the somatic gonad to influence longevity. If this model is correct, then it implies that, under some environmental conditions, the somatic gonad signal is silenced and may no longer be able to counterbalance the signals from the animal's germline. Alternatively, these olfactory neurons could produce a longevity signal in response to a different signal from the somatic gonad. The somatic gonad appears to regulate a pathway that involves DAF-2. Thus, as with the gustatory neurons, it is possible that the olfactory neurons influence longevity by regulating the release of insulin-like peptides (Alcedo, 2004).
Why might sensory neurons influence longevity? One environmental condition, food limitation, is known to have a dramatic effect on life span in many organisms. Caloric restriction extends life span and also delays reproduction. When ample food is restored to calorically-restricted rats, they can reproduce, even at a time when the age-matched controls are post-reproductive or dead. Thus, this response to caloric restriction has obvious survival value, since it allows animals to postpone reproduction until conditions improve. Dauer formation, which is regulated, at least in part, by sensory cues, serves the same function in C. elegans -- it allows animals to postpone reproduction under harsh environmental conditions. No obvious changes were observed in the timing of reproduction in the neuron-ablated animals; however, it is possible that the environmental cues that influence the activities of these neurons in nature also influence other neurons that control reproduction. In this way, sensory cues could affect life span and reproduction coordinately. Alternatively, certain environmental conditions could favor a shorter post-reproductive life span to prevent the aging animals from competing for resources with their progeny. A population of worms that lacks parental competition for resources should, over time, develop a significant advantage relative to populations in which such competition takes place (Alcedo, 2004).
The odr-10 gene encodes an olfactory G protein-coupled receptor that senses diacetyl, an odorant sensed by AWA neurons. odr-10 null mutants are not long-lived, implying that neither diacetyl nor its receptor regulates life span. In contrast, decreasing the mRNA levels of the putative chemosensory G protein-coupled receptor str-2, through RNA-mediated interference, extends life span. This suggests that C. elegans' life span is influenced by its perception of an environmental cue -- as yet unidentified -- that is sensed by STR-2. The identification of sensory cues that influence life span, such as those sensed by STR-2, should make it possible to address this interesting question experimentally (Alcedo, 2004).
Genetic analysis has shown that dos/soc-1/Gab1 functions positively in receptor tyrosine kinase (RTK) stimulated Ras/Map kinase signaling, through the recruitment of csw/ptp-2/Shp2. Using sensitised assays in C. elegans for let-23/Egfr and daf-2/InsR (Insulin receptor-like) signaling, it has been shown that soc-1/Gab1 inhibits phospholipase C-gamma (PLCgamma) and phosphatidylinositol 3'-kinase (PI3K) mediated signaling. Furthermore, as well as stimulating Ras/Map kinase signaling, soc-1/Gab1 stimulates a poorly defined signaling pathway that represses class 2 daf-2 phenotypes. In addition, it is shown that SOC-1 binds the C-terminal SH3 domain of SEM-5. This binding is likely to be functional because the sem-5(n2195)G201R mutation, which disrupts SOC-1 binding, behaves in a qualitatively similar manner to a soc-1 null allele in all assays for let-23/Egfr and daf-2/InsR signaling examined. Further genetic analysis suggests that ptp-2/Shp2 mediates the negative function of soc-1/Gab1 in PI3K mediated signaling, as well as the positive function in Ras/Map kinase signaling. Other effectors of soc-1/Gab1 are likely to inhibit PLCgamma mediated signaling and stimulate the poorly defined signaling pathway that represses class 2 daf-2 phenotypes. Thus, the recruitment of soc-1/Gab1, and its effectors, into the RTK signaling complex modifies the cellular response by enhancing Ras/Map kinase signaling while inhibiting PI3K and PLCgamma mediated signaling (Hopper, 2006).
Development is typically studied as a continuous process under laboratory conditions, but wild animals often develop in variable and stressful environments. C. elegans larvae hatch in a developmentally arrested state (L1 arrest) and initiate post-embryonic development only in the presence of food (E. coli in lab). In contrast to the well-studied dauer arrest, L1 arrest occurs without morphological modification, although larvae in L1 arrest are more resistant to environmental stress than developing larvae. Consistent with its role in dauer formation and aging, insulin/insulin-like growth factor (IGF) signaling is shown to regulate L1 arrest. daf-2 insulin/IGF receptor mutants have a constitutive-L1-arrest phenotype when fed and extended survival of L1 arrest when starved. Conversely, daf-16/FOXO mutants have a defective-arrest phenotype, failing to arrest development and dying rapidly when starved. DAF-16 is required for transcription of the cyclin-dependent kinase inhibitor cki-1 in stem cells in response to starvation, accounting for the failure of daf-16/FOXO mutants to arrest cell division during L1 arrest. Other developmental events such as cell migration, cell fusion, and expression of the microRNA lin-4, a temporal regulator of post-embryonic development, are also observed in starved daf-16/FOXO mutants. These results suggest that DAF-16/FOXO promotes developmental arrest via transcriptional regulation of numerous target genes that control various aspects of development (Baugh, 2006).
Genetic and RNA interference (RNAi) screens for life span regulatory genes have revealed that the daf-2 insulin-like signaling pathway plays a major role in Caenorhabditis elegans longevity. This pathway converges on the DAF-16 transcription factor and may regulate life span by controlling the expression of a large number of genes, including free-radical detoxifying genes, stress resistance genes, and pathogen resistance genes. A genome-wide RNAi screen was conducted to identify genes necessary for the extended life span of daf-2 mutants and ~200 gene inactivations were identified that shorten daf-2 life span. Some of these gene inactivations dramatically shorten daf-2 mutant life span but less dramatically shorten daf-2; daf-16 mutant or wild-type life span. Molecular and behavioral markers for normal aging and for extended life span in low insulin/IGF1 (insulin-like growth factor 1) signaling were assayed to distinguish accelerated aging from general sickness and to examine age-related phenotypes. Detailed demographic analysis, molecular markers of aging, and insulin signaling mutant test strains were used to filter progeric gene inactivations for specific acceleration of aging. Highly represented in the genes that mediate life span extension in the daf-2 mutant are components of endocytotic trafficking of membrane proteins to lysosomes. These gene inactivations disrupt the increased expression of the DAF-16 downstream gene superoxide dismutase sod-3 in a daf-2 mutant, suggesting trafficking between the insulin-like receptor and DAF-16. The activities of these genes may normally decline during aging (Samuelson, 2007).
Insulin signaling is mediated by a complex network of diverging and converging pathways, with alternative proteins and isoforms at almost every step in the process. The two major pathways described to date, which employ insulin receptors as the primary target, include signaling via mitogen-activated protein (MAP) kinases and phosphoinositol-3 kinase (PI3K). The insulin receptor (IR), the first step in these cascades, exists in two isoforms as a result of alternative mRNA splicing of the 11th exon of the insulin proreceptor transcript. The respective sequence coding for 12 amino acids in the C terminus of the alpha chain of the receptor is lacking in A type (IR-A), or Ex11-, whereas it is contained in the B type (IR-B), or Ex11+. To date, no insulin-induced effect has been reported that discriminates signaling via A- and B-type receptors (Leibiger, 2001).
Insulin activates the transcription of its own gene and that of the beta cell glucokinase gene (betaGK) by different mechanisms. Whereas insulin gene transcription is promoted by signaling through insulin receptor A type, PI3K class Ia, and p70s6k, insulin stimulates the betaGK gene by signaling via insulin receptor B type), PI3K class II-like activity, and PKB (c-Akt). These data provide evidence for selectivity in insulin action via the two isoforms of the insulin receptor, the molecular basis being preferential signaling through different PI3K and protein kinases (Leibiger, 2001).
The insulin-like growth factors (IGFs) are well known mitogens, both in vivo and in vitro, while functions in cellular differentiation have also been indicated. A new role for the IGF pathway in regulating head formation has been demonstrated in Xenopus embryos. Both IGF-1 and IGF-2, along with their receptor IGF-1R, are expressed early during embryogenesis, and the IGF-1R is present particularly in anterior and dorsal structures. Overexpression of IGF-1 leads to anterior expansion of head neural tissue as well as formation of ectopic eyes and cement gland, while IGF-1 receptor depletion using antisense morpholino oligonucleotides drastically reduces head structures. Furthermore, IGF signaling exerts this effect by antagonizing the activity of the Wnt signal transduction pathway in the early embryo, at the level of ß-catenin. Thus, the IGF pathway is required for head formation during embryogenesis (Richard-Parpaillon, 2002).
Wnt signaling is involved in numerous developmental processes, such as dorsal axis formation, patterning of the central nervous system, and establishment of cell polarity. The pathway is tightly regulated during embryogenesis and it is becoming increasingly clear that crossregulation between Wnt and other signaling pathways contributes to the complexity and specificity of Wnt activity. For example, retinoid signaling and a specific MAP kinase pathway (TAK/NLK) can both inhibit Wnt activity. However, previous evidence for an interaction between the IGF and the Wnt pathways is limited. IGF-1 stimulation induces a rapid tyrosine-phosphorylation of ß-catenin in a cell line derived from a human colonic adenocarcinoma. It has also been shown that the phosphorylation of ß-catenin induced by IGF-1 leads to a dissociation of the pool of ß-catenin, which is bound to E-cadherin at the plasma membrane, resulting in its relocation to the cytoplasm (Richard-Parpaillon, 2002 and references therein).
However, despite this accumulation of cytoplasmic ß-catenin, no enhancement of Wnt activity is observed after stimulation by IGF-1 alone, as determined by using the Wnt-responsive luciferase reporter construct TOP-FLASH. Recent structural studies might provide an explanation for this paradox. It has been shown that the charged residues involved in this interaction between ß-catenin/E-cadherin are the same as those required for the ß-catenin/ TCF interaction. Thus, this raises the interesting possibility that tyrosine-phosphorylation of ß-catenin, which blocks its association with E-cadherin may also prevent interaction between this molecule and its downstream effector Tcf. This is a potential point at which IGF signaling may inhibit the Wnt pathway. In the future, it will be interesting to investigate this hypothesis further, and also to determine whether the PI3K or the MAPK activated by IGF-1R may be involved in this process (Richard-Parpaillon, 2002).
Peripheral insulin resistance and impaired insulin action are the primary characteristics of type 2 diabetes. The first observable defect in this major disorder occurs in muscle, where glucose disposal in response to insulin is impaired. Insulin-like growth factor-I (IGF-I) and insulin are closely similar in both structure and function, and both can stimulate glucose uptake in muscle. The IGF-I receptor (IGF-IR) represents another potential target to develop useful animal models for human diabetes. A transgenic mouse has been developed with a dominant-negative insulin-like growth factor-I receptor (KR-IGF-IR) specifically targeted to the skeletal muscle. Expression of KR-IGF-IR results in the formation of hybrid receptors between the mutant and the endogenous IGF-I and insulin receptors, thereby abrogating the normal function of these receptors and leading to insulin resistance. Pancreatic ß-cell dysfunction develops at a relative early age, resulting in diabetes. These mice provide an excellent model to study the molecular mechanisms underlying the development of human type 2 diabetes (Fernandez, 2001).
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