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Myosuppressin receptors. Myosuppressin inhibits gut and heart contraction in D. This duplication appears to have occurred prior to the divergence of D. We identified a single ortholog in each mosquito species Figure 2. Specific binding of myosuppressin was also previously shown for the expressed An. A related orphan receptor, OA14, is represented as a single ortholog in the Drosophila, Anopheles , and Culex spp. Other orphan clades. OA12 is most closely related to the proctolin receptor but has expanded in the culicine mosquitoes, with Ae.

OA13 has an uncertain position in Cluster 2 but at least one copy of this gene is found in each of the genomes with the exception of An. Our analysis distinguished nine clades within this class Table 1 ; Figure 3 , of which three have identified ligands: 1 calcitonin-like diuretic hormone CT-DH , 2 corticotropin-releasing factor-like diuretic hormone CRF-DH , and 3 pigment dispersing factor PDF Figure 3. We included the latrophilin GPCRs that are conserved across invertebrates and vertebrates , and bind latrotoxins from spiders in the genus Latrodectus The endogenous ligand for the vertebrate receptors is teneurin-2, a glycoprotein displayed on the surface of cells , however the endogenous ligand in insects in unknown.

Class B secretin GPCRs also include the Methuselah and Methuselah-like genes, which are grouped into four classes, A—D, based on the disulfide bridges present in their extracellular domain Other phylogenetic data for Class B GPCRs have been produced for vertebrates and invertebrates and insects alone This peptide was first identified by its stimulation of pigment dispersal in some arthropods, but in insects PDF was the first neuropeptide shown to regulate circadian activity in D. Its receptor was subsequently identified, and we found single orthologs of this receptor in D.

It is not known whether PDF has a role in circadian activity in insects generally, but host-seeking behavior is one circadian behavior that may be regulated by PDF in mosquitoes Our phylogeny suggests the ancestor of this receptor underwent a duplication event prior to the divergence of the Culicidae and Drosophilidae. Both orthologs from D. These ligands and their associated receptors mediate diuresis by Malpighian tubules Studies in D. Additional mth- like genes were thereafter identified 34 , while genome studies indicate that mth genes are likely present in all insects.

Four major groups A—D of Mth receptors have been proposed on the basis of the disulfide bridges present in their extracellular domains , While present in all insects examined in this study, D. We further note the Drosophila Mth receptors are widely distributed across the tree and are not monophyletic. Only three clades of Mth receptors include members from the Culicidae: the C type Mth, Mth-like 14, and a clade that is sister to the B and D type Mth receptors Figure 3. Cvejic et al. Others, however, report that Mth binds Drosophila sex peptide and other synthetic peptides and suggest this receptor may be a promiscuous GPCR with diverse ligands Each genome contains a single copy of the latrophilin GPCR.

Our analysis suggests these receptors do not form a monophyletic group in the Diptera, but this conclusion is based on poor alignment due to the loss of six of the seven transmembrane domains in the Culicidae. The mosquito receptors, however, retain N-terminal domains that are similar to those of Drosophila spp.

Truncation of the C-terminal region of latrotoxin-binding GPCRs in mammals does not impede responses to latrotoxin in cell culture , which suggests the culicid orthologs may be functional. OB2 was identified as a distant ortholog of the human epididymis six GPCR, itself an orphan, shortly after the publication of the D. EH is a co-activator with ETH of ecdysis behavior in insects. Figure 4. Maximum-likelihood tree of membrane-bound RGCs using the five dipteran species described in Figure 2 with alignments made using the protein kinase domain of each receptor.

This analysis indicated that two of the dipteran orphan clades OGC1 and 3 have no vertebrate ortholog.


Overall, our analysis indicates that dipteran RGCs have undergone few changes, with the possible exceptions of an apparent loss of OGC1 from D. Protein kinase receptors form non-covalently bound dimers upon reaching the cell surface or in response to ligand binding 2. Peptide hormones, growth factors, and membrane proteins are ligands for these receptors, and their interactions, signaling, and function are well characterized for mammalian systems, intermediately characterized for D.

Ligand binding to specific extracellular domains activates intracellular kinase domains that autophosphorylate either tyrosine or serine and threonine residues, presenting docking sites for cytoplasmic effectors, adaptors, and scaffold proteins that in turn activate one or more signal pathways 3. Activated PKRs are also targets of protein phosphatases that modulate and even block signaling in mammals. Similar to the RGCs but unlike the GPCRs, dipteran PKRs have undergone relatively few lineage-specific gains or losses, suggesting that most members were likely present in the most recent common ancestor of culicids and drosophilids.

Figure 5. The tree was rooted using a guanylyl cyclase receptor GI from D. The C. Clades are named after their characterized ligands, if known.

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The RTK clades we identified were conserved across the five dipteran species Figure 5. Ten of these clades are also represented among the 20 recognized subfamilies of human RTKs, which have been classified on the basis of ligand interactions and other features 3. The remaining two RTK clades are known only from insects and other arthropods. One of these is an orphan receptor OR1 , which contains a venus flytrap domain, while the other is the prothoracicotropic hormone PTTH receptor.

Most of the dipteran RTK clades are encoded by a single ortholog in each species. ILP and related receptors. Up to eight ILPs encoded by different genes are known for the dipteran species in our study , and all but the ILP6 subfamily are likely processed into disulfide-linked dimers 6—8 kDa. Only one study from Ae. Several studies also show the IR activates the canonical insulin signaling pathway in Ae. Our analysis supports the presence of OR1 in mosquitoes, other insects, and other invertebrates as well as its loss from the D.

Curated, partial mRNAs indicate this receptor is present in D. The extracellular domain of OR1 contains a venus flytrap domain, which is also found in some GPCRs and RGCs, and has been implicated in binding amino acids and other small molecules , PTTH receptor. Prothoracicotropic hormone regulates molting and development in insects by stimulating the prothoracic glands PGs to produce ecdysteroid hormones — Torso was also shown to interact with Trunk, which is a protein growth factor that regulates early embryonic development.

PTTH expression has been profiled in mosquito larvae — , but it is not known to regulate ecdysteroid production, which occurs in unidentified cells in the abdominal or thoracic wall, not the PGs Other RTKs. The functional significance and signaling of the other RTK clades has been examined in D. The best characterized of them is the EGF receptor, which interacts with one secreted ligand Vein plus three other ligands Spitz, Keren, and Gurken derived from enzymatic cleavage of inactive membrane-bound precursors.

Typically, these ligands regulate the trajectory of specific embryonic and tissue stem cell types , An EGF receptor exists in each mosquito species, and its expression has been characterized in An. However, the putative ortholog in C. The FGF receptor is duplicated in each dipteran species. Functional studies in D. Homolog 1 Heartless, CG interacts only with two of the three related secreted FGFs Pyramus and Thisbe to direct mesoderm migration and heart muscle differentiation of the dorsal vessel, whereas homolog 2 Breathless, CG is activated by its ligand Branchless to define branching of the tracheal system.

Breathless appears to be incompletely annotated, and was removed from our alignments. In general, these ligands act as growth factors and cytokines in both mammals and insects Each clade is represented as a single ortholog in the two Drosophila spp. Duplications have arisen in Ae. In contrast, An. Mammalian activin homologs are also expressed in neuroendocrine cells in the pituitary gland, where they regulate the expression and release of gonadotropic hormones , and in endocrine cells in the pancreas islets, where they modulate insulin secretion An underlying assumption in the study of peptide hormone receptor evolution is that related receptors exhibit a degree of conservation in their active site, as do their peptide ligands.

Insect NPF is a member of the NPY family, and evidence suggests that the neuropeptides regulate related behaviors across these groups Figure 6. Conservation of peptide active sites and receptor binding regions across the Bilateria. Blue shading indicates amino acid similarity between residues according to BLOSUM62 scores; darker shades indicate increased similarity. Yellow bars below residues indicate conservation across the alignment. Position relative to the cell membrane is indicated by the colored line above the alignment: intracellular: green, extracellular: yellow, transmembrane: gray.

Zoomed regions show domains that have been confirmed experimentally to be important for ligand binding by NPYrs. Residues highlighted in red indicate those determined to be involved in ligand binding in H. Binding residues that are highly conserved are listed next to the alignment with their amino acid in human NPYr1 or 2. Only the mature peptide is shown. Coloring is the same as in A. Mutagenesis studies have revealed a number of receptor residues that are involved in NPY binding , We examined the corresponding locations in the dipteran receptors and found that many key binding residues are conserved, including several that are perfectly conserved, since the divergence of protostomes and deuterostomes Mya.

Loops 2—4 comprise a hydrophobic ligand binding pocket in NPY receptors , and within this pocket, multiple residues have been implicated in ligand-receptor interactions 41 — 43 , , Figure 6. The first four residues are absent in the N-terminal truncated C. Q is conserved in all receptors examined except H. Similarly, N is invariant in the dipteran NPF receptors, but differs between vertebrate forms of the receptor.

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In the dipteran receptors, the homologous position is invariantly a glutamic acid with the exception of the truncated C. Although the amino acid at this position is different between the vertebrate and dipteran lineages, the glutamic acid residue still contains a free hydroxyl group, suggesting that the functionality of this position is conserved.

These data overall strongly suggested functional sites are conserved between related but distinct peptides and their associated receptors across hundreds of millions of years of evolution.

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  • This study represents the first comprehensive analysis of the three receptor types that bind peptide hormones and growth factors in insects. Our primary motivation for undertaking this study was to develop a robust phylogenetic framework to study the function of particular orphan receptors in mosquitoes.

    The absence of any individual orphans within the clades of RGCs with characterized ligands suggests these receptors are stable within the Diptera and that diversification of RGCs occurred prior to the evolution of the order several hundred million years ago For Class A GPCRs, most of the orphans in characterized clades are single duplication events that have occurred in a particular mosquito species.

    The functional significance of these duplications is in most cases unclear. Since many peptide hormones exist in multiple forms derived from a single propeptide, we speculate that different forms of a given receptor may preferentially interact with different forms of their cognate peptide hormone.

    In some cases, paralog receptors both bind a single hormone but vary in their binding affinity and phenotypic effect, as is seen in the two PK2 GPCRs of D. Currently, the literature offers no insights into why this bias exists or what the functional significance of so many Methuselah-like GPCRs might be.

    Peptide growth factors and their receptors in the vein wall

    We tried to characterize the evolution of gains and losses of peptide hormone receptors in the Diptera but in many cases it was not possible to discern such events with certainty due to issues with annotation. Often what initially appeared as a gene duplication event was in fact two separate gene annotations for a single gene.

    This was verified in some cases by available RNAseq data covering the genes of interest, whereas in others, alignment to a single ortholog demonstrated that the actual gene had been divided during gene prediction. We had to omit some GPCRs from the analyses due to absence of the domain needed for identification and alignment. Several potential PKRs also lacked a complete kinase domain and were therefore removed from our analysis. Though care was taken to correct these annotation errors in our analysis, it is possible that some duplication events we report are artifacts of gene prediction algorithms.

    Studies across a range of organisms have shown the utility of comparing orphan to characterized receptors. Hansen and colleagues 59 demonstrated that an orphan GPCR was sister to the AKH receptor, and these two receptors were sister to the corazonin receptor. Subsequent efforts to deorphanize the receptor identified a structurally intermediate peptide encoded in the genome of insects.

    Our results illuminate several orphan clades and individual receptors that are sister to characterized receptors, suggesting that these orphans may bind similar ligands. Additionally, the species distribution of orphan receptors and patterns of tissue and temporal expression may also reduce the target ligand pool, and hopefully aid in deorphanization.

    Thus, our results could assist in deorphanizing receptors in newly sequenced mosquito genomes by identifying their ligands. On the other hand, the literature is more equivocal in regard to sequence similarity between species also resulting in functional similarity. Thus, in addition to deorphanization, considerable work remains in understanding the physiological function of many peptide hormones and growth factors among different species of mosquitoes and other insects. Kevin J. Vogel, Mark R. Brown, and Michael R. Strand designed the study, Kevin J.

    Vogel performed the analyses, and Kevin J. Strand wrote the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors thank Joe W. Crim for helpful comments on earlier versions of the manuscript. Brown and Michael R. Receptor tyrosine kinase signaling — a proteomic perspective.

    Adv Enzyme Regul 51 — Potter LR. Regulation and therapeutic targeting of peptide-activated receptor guanylyl cyclases. Pharmacol Ther — Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell — CrossRef Full Text. Mass spectrometric profiling of neuro -peptides in the worker honeybee, Apis mellifera. Neuropharmacology 58 — Exploring the Caenorhabditis elegans and Drosophila melanogaster genomes to understand neuropeptide and peptidase function.

    Biochem Soc Trans 28 —9. Genomics and peptidomics of neuropeptides and protein hormones present in the parasitic wasp Nasonia vitripennis. J Proteome Res 9 — Neuropeptides and neuropeptide receptors in the Drosophila melanogaster genome. Genome Res 11 — From the genome to the proteome: uncovering peptides in the Apis brain.

    Science —9. Neuropeptidomics of the mosquito Aedes aegypti. Neuropeptides and peptide hormones in Anopheles gambiae. Science —5. The unique evolution of neuropeptide genes in the silkworm Bombyx mori. Insect Biochem Mol Biol 38 — Prediction of neuropeptide cleavage sites in insects. Bioinformatics 24 — In silico cloning of genes encoding neuropeptides, neurohormones and their putative G-protein coupled receptors in a spider mite.

    Insect Biochem Mol Biol 42 — Genomics, transcriptomics, and peptidomics of neuropeptides and protein hormones in the red flour beetle Tribolium castaneum. Genome Res 18 — Structure-activity and immunochemical data provide evidence of developmental- and tissue-specific myosuppressin signaling. Peptides 36 —9. Identifying neuropeptide and protein hormone receptors in Drosophila melanogaster by exploiting genomic data. Brief Funct Genomic Proteomic 4 — Prog Neurobiol 80 :1— Front Neuroendocrinol 29 — Identification and functional characterization of two orphan G-protein-coupled receptors for adipokinetic hormones from silkworm Bombyx mori.

    J Biol Chem — Neuropeptide receptor transcriptome reveals unidentified neuroendocrine pathways. PLoS One 3 :e The G protein-coupled receptors in the silkworm, Bombyx mori. Insect Biochem Mol Biol 40 — Drosophila neuropeptide signaling. Adv Genet 49 :1— Molecular identification of a myosuppressin receptor from the malaria mosquito Anopheles gambiae. Biochem Biophys Res Commun — G protein coupled receptors in Anopheles gambiae.

    Science —8. Metpally RP, Sowdhamini R. Cross genome phylogenetic analysis of human and Drosophila G protein-coupled receptors: application to functional annotation of orphan receptors. BMC Genomics 6 The genome sequence of the malaria mosquito Anopheles gambiae. Science — Genome sequence of Aedes aegypti , a major arbovirus vector. Sequencing of Culex quinquefasciatus establishes a platform for mosquito comparative genomics. Feeding and the rhodopsin family g-protein coupled receptors in nematodes and arthropods. Front Endocrinol Lausanne 3 Joost P, Methner A.

    Phylogenetic analysis of human G-protein-coupled receptors as a tool for the prediction of orphan receptor ligands. Eddy SR. Accelerated profile HMM searches. PLoS Comput Biol 7 :e OrthoDB: the hierarchical catalog of eukaryotic orthologs in Nucleic Acids Res 39 :D—8. Fingerprinting G-protein-coupled receptors. Protein Eng 7 — Brody T, Cravchik A. Drosophila melanogaster G protein-coupled receptors.

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    J Cell Biol :F83—8. Frickey T, Lupas A. Bioinformatics 20 —4. MAFFT version 5: improvement in accuracy of multiple sequence alignment. Nucleic Acids Res 33 —8. Edgar RC.

    Peptide Growth Factors and Their Receptors I

    Nucleic Acids Res 32 —7. Jalview version 2 — a multiple sequence alignment editor and analysis workbench. Bioinformatics 25 — New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.

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    • Syst Biol 59 — Merten N, Beck-Sickinger A. In: Zukowska Z, Feuerstein G, editors. Regul Pept —9. Reciprocal mutations of neuropeptide Y receptor Y2 in human and chicken identify amino acids important for antagonist binding. FEBS Lett :5—9. Neuropeptides 45 — Time flies, a new molecular time-scale for brachyceran fly evolution without a clock. Syst Biol 52 — Analysis of the complete mitochondrial DNA from Anopheles funestus : an improved dipteran mitochondrial genome annotation and a temporal dimension of mosquito evolution.

      Mol Phylogenet Evol 39 — Phylogenetic analysis and temporal diversification of mosquitoes Diptera: Culicidae based on nuclear genes and morphology. BMC Evol Biol 9 The G protein-coupled receptor repertoires of human and mouse. An evolutionary comparison of leucine-rich repeat containing G protein-coupled receptors reveals a novel LGR subtype.

      Peptides 34 — Endocrinology — Bursicon, the insect cuticle-hardening hormone, is a heterodimeric cystine knot protein that activates G protein-coupled receptor LGR2. Drosophila molting neurohormone bursicon is a heterodimer and the natural agonist of the orphan receptor DLGR2. FEBS Lett —6. Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes.

      Rapid, nongenomic responses to ecdysteroids and catecholamines mediated by a novel Drosophila G-protein-coupled receptor. J Neurosci 25 — Anopheles gambiae corazonin: gene structure, expression and effect on mosquito heart physiology. Insect Mol Biol 21 — J Exp Biol — Identified peptidergic neurons in the Drosophila brain regulate insulin-producing cells, stress responses and metabolism by coexpressed short neuropeptide F and corazonin.

      Cell Mol Life Sci 69 — Drosophila neuropeptides in regulation of physiology and behavior. Prog Neurobiol 92 — Discovery of a novel insect neuropeptide signaling system closely related to the insect adipokinetic hormone and corazonin hormonal systems. Deletion of the ecdysis-triggering hormone gene leads to lethal ecdysis deficiency. Development — Pubmed Abstract Pubmed Full Text. The adipokinetic hormone system in Culicinae Diptera: Culicidae : molecular identification and characterization of two adipokinetic hormone AKH precursors from Aedes aegypti and Culex pipiens and two putative AKH receptor variants from Ae.

      Insect Biochem Mol Biol 39 — Kaufmann C, Brown MR. Regulation of carbohydrate metabolism and flight performance by a hypertrehalosaemic hormone in the mosquito Anopheles gambiae. J Insect Physiol 54 — Gen Comp Endocrinol —7. Open conformation of adipokinetic hormone receptor from the malaria mosquito facilitates hormone binding. Peptides 32 —9. Functional characterization of an allatotropin receptor expressed in the corpora allata of mosquitoes. Peptides 34 —8. Insulin production and signaling in renal tubules of Drosophila is under control of tachykinin-related peptide and regulates stress resistance.

      PLoS One 6 :e Identification of the Drosophila and Tribolium receptors for the recently discovered insect RYamide neuropeptides. Identification of the endogenous cysteine-rich peptide trissin, a ligand for an orphan G protein-coupled receptor in Drosophila. Biochem Biophys Res Commun —8. Expression and functional characterization of a Drosophila neuropeptide precursor with homology to mammalian preprotachykinin A. Regulation of insulin-producing cells in the adult Drosophila brain via the tachykinin peptide receptor DTKR.

      J Exp Biol —8. Role of tachykinin-related peptide signaling in response to metabolic stress. J Neurogenet 20 3—4 Cloning, heterologous expression and developmental regulation of a Drosophila receptor for tachykinin-like peptides. EMBO J 10 —9. Characterization and distribution of NKD, a receptor for Drosophila tachykinin-related peptide 6. Peptides 30 — Functional comparison of two evolutionary conserved insect neurokinin-like receptors.

      Peptides 28 —8. Tachykinin-related peptides and their receptors in invertebrates: a current view. Peptides 31 —4. Natalisin, a tachykinin-like signaling system, regulates sexual activity and fecundity in insects. Transcellular and paracellular pathways of transepithelial fluid secretion in Malpighian renal tubules of the yellow fever mosquito Aedes aegypti. Acta Physiol — A biogenic amine and a neuropeptide act identically: tyramine signals through calcium in Drosophila tubule stellate cells.

      Proc Biol Sci Mosquito Aedes aegypti L. FEBS Lett — The kinin receptor is expressed in the Malpighian tubule stellate cells in the mosquito Aedes aegypti L. Insect Biochem Mol Biol 41 — Systematic G-protein-coupled receptor analysis in Drosophila melanogaster identifies a leucokinin receptor with novel roles.

      J Biol Chem 41 —7. A comparative review of short and long neuropeptide F signaling in invertebrates: any similarities to vertebrate neuropeptide Y signaling? Peptides 32 — Characterization of neuropeptide F and its receptor from the African malaria mosquito, Anopheles gambiae. Peptides 26 — The anterior stomach of larval mosquitoes Aedes aegypti : effects of neuropeptides on transepithelial ion transport and muscular motility.

      J Exp Biol —9. Neuropeptide F and its expression in the yellow fever mosquito, Aedes aegypti. Peptides 23 — Isolation and characterization of ovarian ecdysteroidogenic hormones from the mosquito, Aedes aegypti. Insect Biochem 19 —6. J Med Entomol 39 — Endogenous regulation of mosquito host-seeking behavior by a neuropeptide. J Insect Physiol 40 — The host-seeking inhibitory peptide, Aea-HP-1, is made in the male accessory gland and transferred to the female during copulation.

      Peptides 34 —7. Characterization of a functional neuropeptide F receptor from Drosophila melanogaster. Characterization of the short neuropeptide F receptor from Drosophila melanogaster. Functional and genetic characterization of neuropeptide Y-like receptors in Aedes aegypti. Molecular identification of the first SIFamide receptor. Biochem Biophys Res Commun —9. Stay B, Tobe SS. The role of allatostatins in juvenile hormone synthesis in insects and crustaceans. Annu Rev Entomol 52 — Allatostatins: a growing family of neuropeptides with structural and functional diversity.

      Ann N Y Acad Sci — Molecular cloning and genomic organization of a second probable allatostatin receptor from Drosophila melanogaster. Biochem Biophys Res Commun —7. Neuropeptides in the nervous system of Drosophila and other insects: multiple roles as neuromodulators and neurohormones.

      Prog Neurobiol 68 :1— A single cDNA encodes all three Aedes leucokinins, which stimulate both fluid secretion by the Malpighian tubules and hindgut contractions. J Biol Chem —7. Functional annotation of two orphan G-protein-coupled receptors, Drostar1 and -2, from Drosophila melanogaster and their ligands by reverse pharmacology. Allatostatin-C receptors in mosquitoes. Peptides 31 — Regul Pept — We also tested the effect of FGF2 on neurite outgrowth from CGNs under the same conditions used for dekafins, and found that FGF2 statistically significantly stimulated neurite outgrowth, although with a lower efficacy than dekafin2 Fig.

      The ability of FGF1 to interfere with dekafin neuritogenic activity subsequently was tested. Thus, dekafin activation of FGFRs in neurons may result in neuronal differentiation as reflected by neurite extension. The present study therefore tested whether the dekafins promote neuronal cell survival. Moreover, treatment with dekafin6, 8, 9, and 17, but not with dekafin1, 2, 3, 5, or 10, dose dependently promoted CGN survival Fig. At a higher concentration 0. These results indicate that activation of FGFR in CGNs under certain conditions may lead to either an increase or a decrease of neuronal survival depending on the particular dekafin and concentration used.

      Effect of dekafins on survival of cerebellar granule neurons CGNs induced to undergo apoptosis. Low KCl: cells induced to undergo apoptosis. The basic residues of dekafin1 were found to be important for FGFR binding. Recent studies indicate that FGF23 is a hormone that regulates serum phosphate level in contrast to other FGF family members that act as local factors. Thus, the absence of the dekafin motif in FGF15, 19, and 23 may reflect the specificity of their receptor interaction profiles.

      The effect of dekafins on receptor activation was transient and dose dependent, and higher peptide concentrations tended to be less effective. The transient nature of FGFR activation by the peptides could reflect receptor desensitization because of e. Dekafins were prepared as peptide dendrimers composed of four monomers coupled to a lysine backbone. Differences in the neuritogenic potential displayed by the growth factors and the derived peptides might be because of the higher complexity of the FGF—FGFR binding interface than the peptide—FGFR interaction site, resulting in different receptor activation kinetic properties and subsequent interactions of the activated receptor with downstream signaling molecules.

      In contrast to their neuritogenic potential, only four of the tested peptides, dekafin6, 8, 9, and 17, promoted survival of primary neurons induced to undergo apoptosis Fig. This indicates that mimetics of FGF8, 9, and 17 may be expected to have neuroprotective effects in vivo. However, dekafin1 and 2 did not protect CGNs induced to undergo apoptosis by potassium chloride withdrawal. At high concentrations, these peptides and dekafin3, 5, 6, and 8 even reduced CGN survival Fig.

      Thus, FGF2 at low concentrations was shown to stimulate survival and differentiation, but inhibit 3T3 fibroblast proliferation. In contrast, at intermediate concentrations it stimulated proliferation of the same cell type in the presence of serum, but stimulated apoptosis if serum was withdrawn. High FGF2 concentrations reversed the proliferative and apoptotic effects and mirrored the low concentration effects, namely inhibition of proliferation and stimulation of survival and differentiation. Tyr first, then Tyr, etc. Activation of receptor tyrosine kinases has been shown to require specific orientations of the kinase domains depending on optimal rotational positioning of the individual receptor molecules within a dimer.

      In addition to differences in receptor occupancy, the differences in receptor activation by FGF and the various dekafins might be due to deviations from the optimal rotational positioning of the individual receptor following the binding of different ligands. In summary, the present study characterized dekafin peptides derived from a specific region of FGF that are capable of inducing neuronal differentiation and, in some cases, survival. Dekafins appear to act as FGFR partial agonists with possible therapeutic potential.

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      FGFRs , fibroblast growth factor receptors. Figure 3 Open in figure viewer PowerPoint. Figure 4 Open in figure viewer PowerPoint. Figure 5 Open in figure viewer PowerPoint. Dekafins are partial agonists of FGFR The present study next tested whether dekafin peptides could compete with FGF1 with regard to receptor activation.

      Figure 6 Open in figure viewer PowerPoint. Figure 7 Open in figure viewer PowerPoint. Figure 8 Open in figure viewer PowerPoint. Figure 9 Open in figure viewer PowerPoint. Bell C. Cell 11 , — Citing Literature. Volume , Issue 3 February Pages Figures References Related Information.