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At least 19 recordsLinked to original sources
PubMed1998

Characterization of pig connective tissue growth factor (CTGF) cDNA, mRNA and protein from uterine tissue.

Connective tissue growth factor (CTGF) is a 38kDa mitogen and chemotactic factor for fibroblasts that is transcriptionally activated by serum or transforming growth factor-beta and may play a role in wound healing and various skin diseases. In these studies, pig endometrium was shown to contain a single CTGF transcript of 2.4kb and to produce a 38kDa CTGF-immunoreactive protein. Cloning and sequencing of a 1.5kb pig uterine CTGF cDNA revealed that the predicted pCTGF primary translation product displayed 92% identity to human CTGF and 93% identity to mouse CTGF. The pCTGF cDNA encoded a 26 amino acid signal peptide followed by a 323-residue sequence containing 38 highly conserved cysteine residues. In common with mouse and human CTGF proteins, pCTGF is predicted to resemble a multi-functional mosaic protein that contains four distinct modules.

Amino Acid Sequence↗
PubMed1990

Primary structure of a pheromone-binding protein from Antheraea pernyi: homologies with other ligand-carrying proteins.

An antennal cDNA clone encoding the complete sequence (163 amino acids) of a pheromone-binding protein precursor from the male silk moth, Antheraea pernyi, was isolated using oligonucleotide probes. The cloned cDNA was expressed and the translation product detected by specific antibodies. The deduced protein sequence consists of a signal peptide of 21 amino acids and a mature binding protein of 142 amino acid residues. The predicted structure of this protein is homologous to binding-proteins from different insect species which have previously been identified, but shows no similarities to odorant-binding proteins from vertebrates, suggesting that soluble odorant-binding proteins in insects and vertebrates represent an evolutionary convergence.

Amino Acid Sequence↗
PubMed2005

Constitutive secretion of protease nexin-1 by glial cells and its regulation by G-protein-coupled receptors.

Extracellular serine proteases and their inhibitors (serpins) play a key role for synaptic plasticity in the developing and adult CNS. Serpins also counteract the extravasated proteases during brain injury. We studied the mechanisms by which one of the most important serpins, serpinE2 or protease nexin-1 (PN-1), is secreted by glial cells and how its secretion is regulated by extracellular signals. Using time-lapse videomicroscopy and biochemical methods, we demonstrate that PN-1 is constitutively secreted through small vesicles animated by a discontinuous movement using microtubules as tracks. The F-actin network underneath the plasma membrane acting as a barrier hindered PN-1 vesicle exocytosis. Vasointestinal/pituitary adenylate cyclase peptides and the G-protein activator mastoparan increased PN-1 secretion by disrupting the F-actin barrier. The receptor-mediated regulation of PN-1 constitutive secretion may be an important mechanism adapting extracellular proteolytic activity to synaptic activity.

Actins↗
PubMed2005

Alternative protein secretion: the Mam1 ABC transporter supports secretion of M-factor linked GFP in fission yeast.

To examine whether the fission yeast Mam1 ABC transporter can be used for secretion of heterologous proteins, thereby bypassing the classical secretion pathway, we have analyzed chimeric forms of the M-factor precursor. It was demonstrated that GFP can be exported when fused to both the amino-terminal prosequence from mfm1 and a CaaX motif. This secretion was dependent on the Mam1 transporter and not the classical secretion pathway. The secretion efficiency of GFP, however, was relatively low and most of the reporter protein was trapped in the vacuolar membranes. Our findings suggest that the Mam1 ABC protein is a promiscuous peptide transporter that can accommodate globular proteins of a relatively large size. Furthermore, our results help in defining the sequences required for processing and secretion of natural M-factor.

ATP-Binding Cassette Transporters↗
PubMed1998

G protein-bound conformation of mastoparan-X: heteronuclear multidimensional transferred nuclear overhauser effect analysis of peptide uniformly enriched with 13C and 15N.

Mastoparans, a family of tetradecapeptides from wasp venom, have been used as convenient low molecular weight models of receptors coupled to GTP-binding regulatory proteins (G proteins) for the understanding of the interaction between G proteins and receptors. Sukumar and Higashijima have analyzed the conformation of mastoparan-X (MP-X) bound to the G protein alpha-subunit using proton two-dimensional transferred nuclear Overhauser effect (TRNOE) spectroscopy [Sukumar, M., and Higashijima, T. (1992) J. Biol. Chem., 267, 21421-21424]. The resultant structure, however, was not well-defined due to severe overlap of peptide proton resonances. To determine the G protein-bound conformation of MP-X in detail, we have analyzed this interaction by heteronuclear multidimensional TRNOE experiments of MP-X uniformly enriched with 15N and/or 13C. By solving the overlap problem, we were able to determine the precise conformation of MP-X bound to Gi1alpha: the peptide adopts an amphiphilic alpha-helix from Trp3 to C-terminal Leu14, and the atomic root-mean-square deviation (rmsd) values in this portion about the averaged coordinates were 0.27 +/- 0.07 A for the backbone atoms (N, Calpha, C') and 0.84 +/- 0.16 A for all heavy atoms. These values are much smaller than the corresponding rmsd values of the structures obtained from the proton 2D TRNOE spectrum alone: 1.70 +/- 0.41 A for the backbone atoms (N, Calpha, C') and 2.84 +/- 0.51 A for all heavy atoms. Our results indicate that the heteronuclear multidimensional TRNOE experiments of peptides uniformly enriched with stable isotopes are a very powerful tool for analyzing the conformation of short peptides bound to large proteins. We will also discuss the structure-activity relationships of mastoparans in activating G proteins on the basis of the precise structure of MP-X bound to Gi1alpha.

Amino Acid Sequence↗
PubMed2006

Nuclear addressing provides a clue for the transforming activity of amino-truncated CCN3 proteins.

CCN3 is a founding member of the CCN (Cyr61, Ctgf, Nov) family of cell growth and differentiation regulators. These secreted proteins are key regulators in embryonic development, and are associated with severe pathologies including fibrotic diseases and cancers. CCN3 was discovered as a MAV integration site in an avian nephroblastoma. Previous work established that the amino-truncated protein expressed in this tumor was inducing morphological transformation of chicken embryo fibroblasts, whereas the full-length secreted CCN3 protein was inhibiting cell growth. Amino-truncated variants were identified in cancer cell lines. Since the lack of signal peptide was expected to alter the fate of the truncated proteins, we hypothesized that modifications of CCN3 subcellular addressing could be responsible for the oncogenic activities of CCN3. The CCN proteins are composed of four structural modules (IGFBP, TSP1, VWC, and CT). We report that amino-truncated variants of CCN3 are addressed to the nucleus and that the carboxyterminal (CT) module of CCN3 is responsible for the nuclear addressing. Furthermore, our data identify nuclear CCN3 variants as potential transcriptional regulators. In this context, the CT module confers on nuclear CCN3 proteins a negative regulatory effect on transcription. We propose that the nuclear localization of amino-truncated CCN3 proteins be correlated to oncogenicity.

Animals↗
PubMed2003

Induction of pro-angiogenic signaling by a synthetic peptide derived from the second intracellular loop of S1P3 (EDG3).

The G-protein-coupled receptors of the endothelial differentiation gene (EDG) family mediate pro-angiogenic activities, such as endothelial cell proliferation, chemotaxis, and vessel morphogenesis. We synthesized and tested the effects of a 9-amino acid peptide (KRX-725), derived from the second intracellular loop of S1P3 (EDG3). KRX-725 mimics the effects of sphingosine 1-phosphate (S1P), the natural ligand of S1P3, by triggering a Gi-dependent MEK-ERK (mitogen-activated protein kinase kinase and extracellular signal-regulated kinase) signal transduction pathway. Using aortic rings as an ex vivo model of angiogenesis, vascular sprouting was assessed in the presence of KRX-725 or S1P. KRX-725 induced extensive and dense vascular sprouts, which contain an elaborated organization of endothelial and smooth muscle layers, including lumen formation. When KRX-725 or S1P was combined with proangiogenic factors, such as basic fibroblast growth factor (bFGF), stem cell factor, or vascular endothelial growth factor, the effect was synergistic, leading to further enhancement of vascular sprouting. KRX-725 also initiated neovascularization in a mouse corneal pocket assay in vivo and showed synergism with bFGF. The specificity of KRX-725 was demonstrated via peptide-induced receptor internalization of S1P3 but not S1P1. The ability of a short peptide to stimulate extensive angiogenesis and to synergize with pro-angiogenic factors suggests that KRX-725 may serve as a useful agent in treating pathologic conditions such as peripheral vascular disease, cardiac ischemia, or tissue grafts.

Animals↗
PubMed1997

Trimeric G proteins control exocytosis in chromaffin cells. Go regulates the peripheral actin network and catecholamine secretion by a mechanism involving the small GTP-binding protein Rho.

Besides having a role in signal transduction, heterotrimeric G proteins may be involved in membrane trafficking events. In chromaffin cells, Go is associated with secretory organelles and its activation by mastoparan inhibits the ATP-dependent priming of exocytosis. The effectors by which Go controls exocytosis are currently unknown. The subplasmalemmal actin network is one candidate, since it modulates secretion by controlling the movement of secretory granules to the plasma membrane. In streptolysin-O-permeabilized chromaffin cells, activation of exocytosis produces disassembly of cortical actin filaments. Mastoparan blocks the calcium-evoked disruption of cortical actin, and this effect is specifically inhibited by antibodies against Galphao and by a synthetic peptide corresponding to the COOH-terminal domain of Galphao. Disruption of actin filaments with cytochalasin E and Clostridium perfringens iota toxin partially reverses the mastoparan-induced inhibition of secretion. Furthermore, the effects of mastoparan on cortical actin and exocytosis are greatly reduced in cells treated with Clostridium botulinum C3 exoenzyme, which specifically inactivates the small G protein Rho. We propose that the control exerted by the granule-associated Go on exocytosis may be related to effects on the cortical actin network through a sequence of events which eventually involves the participation of Rho.

ADP Ribose Transferases↗
PubMed1991

Specific activation of Gs by synthetic peptides corresponding to an intracellular loop of the beta-adrenergic receptor.

Peptides corresponding to the amino acid sequence of the hamster beta 2-adrenergic receptor (beta 2AR) were synthesized and their ability to activate purified G-proteins determined. Two peptides, comprising the N- and C-terminal 15 amino acids of the putative third intracellular loop region of the beta 2AR were found to activate the G-protein Gs but not to activate a preparation of Gi/Go. Other peptides corresponding to the internal portions of this loop and the C-terminal tail region failed to activate either G-protein. The presence of phospholipid vesicles was required for this activation. The observation that peptides with sequences corresponding to the ends of the third intracellular loop of the beta AR can specifically activate Gs confirms the results of previous mutagenesis studies on the receptor and demonstrates that the secondary structure conferred by the amino acid sequences in these regions is sufficient for the activation of G-proteins.

Amino Acid Sequence↗
PubMed1998

Phosrestide-1, a peptide derived from the Drosophila photoreceptor protein phosrestin I, is a potent substrate for Ca2+/calmodulin-dependent protein kinase II from rat brain.

Multifunctional Ca2+/calmodulin-dependent protein kinase type II (CaMK II) plays a crucial role in mediation of cellular responses to rising cytosolic Ca2+ levels. We find that the novel peptide substrate PGTIEKKRSNAMKKMKSIEQHR serves as a highly potent substrate for CaMK II enzymes purified from both Drosophila and rat. The peptide is derived from a photoreceptor-specific protein, phosrestin I, of the Drosophila compound eye and is designated as phosrestide-1. Using saturating substrate concentrations, the enzymes from both species transfer the gamma-phosphoryl group of ATP to phosrestide-1 at a level three to ten times greater than to the commercially available mammalian-derived CaMK II substrates, autocamtide-3 and syntide-2. This indicates a conservation of substrate preferences for CaMK II derived from distantly related species, a dipteran fly and a mammal. Although phosrestide-1 contains two potential serine residues for CaMK II phosphorylation, we find that only the C-terminal serine is phosphorylated by rat CaMK II. However, removal of the upstream sequence containing the N-terminal serine substantially reduced the potency of phosrestide-1 as a CaMK II substrate to a level comparable to that of syntide-2 or autocamtide-3. We also find that a peptide representing the N-terminal segment of phosrestide-1 does not inhibit either CaMK II. Therefore, the enhanced potency of phosrestide-1 as a CaMK II substrate is likely to be due to a preferred conformation of the peptide induced by the N-terminal segment rather than to a specific binding of the enzymes to the N-terminus of the peptide. To the best of our knowledge, phosrestide-1 is the first CaMK II substrate which is designed based on an invertebrate sequence. The high phosphorylation level of phosrestide-1 by CaMK II of mammalian origin may reflect highly conserved CaMK II signaling cascades between vertebrates and invertebrates.

Amino Acid Sequence↗
PubMed1997

Connective tissue growth factor. Friend or foe?

Connective tissue growth factor (CTGF) is a novel cysteine-rich, secreted peptide, which is implicated in human atherosclerosis and fibrotic disorders such as systemic scleroderma. CTGF is a member of the peptide family that includes serum-induced immediate early gene products, a v-src-induced peptide, and a putative proto-oncogene. The CTGF gene family is a modular protein and is conserved throughout evolution. CTGF mRNA has been found in the human, mouse, chicken, frog, and fly. The functions of the CTGF gene family include embryogenesis, wound healing, and regulation of extracellular matrix production. Human CTGF is undetectable in normal blood vessels but overexpressed in atherosclerotic lesions, suggesting an important role in atherogenesis.

Connective Tissue Growth Factor↗
PubMed2000

Bioactive motifs of agouti signal protein.

The switch between the synthesis of eu- and pheomelanins is modulated by the interaction of two paracrine signaling molecules, alpha-melanocyte stimulating hormone (MSH) and agouti signal protein (ASP), which interact with melanocytes via the MSH receptor (MC1R). Comparison of the primary sequence of ASP with the known MSH pharmacophore provides no suggestion about the putative bioactive domain(s) of ASP. To identify such bioactive motif(s), we synthesized 15-mer peptides that spanned the primary sequence of ASP and determined their effects on the melanogenic activities of murine melanocytes. Northern and Western blotting were used, together with chemical analysis of melanins and enzymatic assays, to identify three distinct bioactive regions of ASP that down-regulate eumelanogenesis. The decrease in eumelanin production was mediated by down-regulation of mRNA levels for tyrosinase and other melanogenic enzymes, as occurs in vivo, and these effects were comparable to those elicited by intact recombinant ASP. Shorter peptides in those motifs were synthesized and their effects on melanogenesis were further investigated. The amino acid arginine, which is present in the MSH peptide pharmacophore (HFRW), is also in the most active domain of ASP (KVARP). Our data suggest that lysines and an arginine (in motifs such as KxxxxKxxR or KxxRxxxxK) are important for the bioactivity of ASP. Identification of the specific ASP epitope that interacts with the MC1R has potential pharmacological applications in treating dysfunctions of skin pigmentation.

Agouti Signaling Protein↗
PubMed1995

Activation of G proteins bidirectionally affects apoptosis of cultured cerebellar granule neurons.

Cultured cerebellar granule neurons maintained in depolarizing concentrations of K+ (25 mM) and then switched to physiological concentrations of K+ (5 mM) undergo apoptosis. We now report that activation of specific G proteins robustly and bidirectionally affects apotosis of cultured rat cerebellar granule neurons. Stimulation of Gs with cholera toxin completely blocks apoptosis induced by nondepolarizing concentrations of K+, whereas stimulation of Go/Gi with the wasp venom peptide mastoparan induces apoptosis of cerebellar granule neurons even in high (depolarizing) concentrations of K+. Moreover, pretreatment of cerebellar granule neurons with cholera toxin attenuates neuronal death induced by mastoparan. By contrast, pertussis toxin, cell-permeable analogues of cyclic AMP, and activators of protein kinase A do not affect apoptosis of cultured cerebellar granule neurons. These data suggest that G proteins may function as key switches for controlling the programmed death of mammalian neurons, especially in the developing CNS.

Animals↗
PubMed2002

Trichoderma atroviride G-protein alpha-subunit gene tga1 is involved in mycoparasitic coiling and conidiation.

The soil fungus Trichoderma atroviride, a mycoparasite, responds to a number of external stimuli. In the presence of a fungal host, T. atroviride produces hydrolytic enzymes and coils around the host hyphae. In response to light or nutrient depletion, asexual sporulation is induced. In a biomimetic assay, different lectins induce coiling around nylon fibers; coiling in the absence of lectins can be induced by applying cyclic AMP (cAMP) or the heterotrimeric G-protein activator mastoparan. We isolated a T. atroviride G-protein alpha-subunit (Galpha) gene (tgal) belonging to the fungal subfamily with the highest similarity to the Galpha1 class. Generated transgenic lines that overexpress Galpha show very delayed sporulation and coil at a higher frequency. Furthermore, transgenic lines that express an activated mutant protein with no GTPase activity do not sporulate and coil at a higher frequency. Lines that express an antisense version of the gene are hypersporulating and coil at a much lower frequency in the biomimetic assay. The loss of Tgal in these mutants correlates with the loss of GTPase activity stimulated by the peptide toxin Mas-7. The application of Mas-7 to growing mycelial colonies raises intracellular cAMP levels, suggesting that Tgal can activate adenylyl cyclase. In contrast, cAMP levels and cAMP-dependent protein kinase activity drop when diffusible host signals are encountered and the mycoparasitism-related genes ech42 and prb1 are highly expressed. Mycoparasitic signaling is unlikely to be a linear pathway from host signals to increased cAMP levels. Our results demonstrate that the product of the tga1 gene is involved in both coiling and conidiation.

Base Sequence↗
PubMed2003

Identification of a novel integrin alphaMbeta2 binding site in CCN1 (CYR61), a matricellular protein expressed in healing wounds and atherosclerotic lesions.

CCN1 (cysteine-rich 61) and CCN2 (connective tissue growth factor) are growth factor-inducible immediate-early gene products found in atherosclerotic lesions, restenosed blood vessels, and healing cutaneous wounds. Both CCN proteins have been shown to support cell adhesion and induce cell migration through interaction with integrin receptors. Recently, we have identified integrin alphaMbeta2 as the major adhesion receptor mediating monocyte adhesion to CCN1 and CCN2 and have shown that the alphaMI domain binds specifically to both proteins. In the present study, we demonstrated that activated monocytes adhered to a synthetic peptide (CCN1-H2, SSVKKYRPKYCGS) derived from a conserved region within the CCN1 C-terminal domain, and this process was blocked by the anti-alphaM monoclonal antibody 2LPM19c. Consistently, a glutathione S-transferase (GST) fusion protein containing the alphaMI domain (GST-alphaMI) bound to immobilized CCN1-H2 as well as to the corresponding H2 sequence in CCN2 (CCN2-H2, TSVKTYRAKFCGV). By contrast, a scrambled CCN1-H2 peptide and an 18-residue peptide derived from an adjacent sequence of CCN1-H2 failed to support monocyte adhesion or alphaMI domain binding. To confirm that the CCN1-H2 sequence within the CCN1 protein mediates alphaMbeta2 interaction, we developed an anti-peptide antibody against CCN1-H2 and showed that it specifically blocked GST-alphaMI binding to intact CCN1. Collectively, these results identify the H2 sequence in CCN1 and CCN2 as a novel integrin alphaMbeta2 binding motif that bears no apparent homology to any alphaMbeta2 binding sequence reported to date.

Amino Acid Motifs↗
PubMed1998

Signal transduction pathways leading to spore differentiation in Dictyostelium discoideum.

Cells that overexpress PKA as a consequence of carrying multiple copies of the gene encoding the catalytic subunit can be induced to sporulate when developing as single cells. A peptide phosphorylated by PKA, termed SDF-1, has recently been shown to stimulate this process (Anjard et al., 1997). Several genes have been implicated in a signal transduction pathway by which prestalk cells induce encapsulation of prespore cells during terminal differentiation including a prestalk-specific putative membrane protease (TagC) and a two-component system consisting of a receptor-histidine kinase (DhkA) and a response regulator with cAMP phosphodiesterase activity (RegA). To determine whether SDF-1 uses this pathway, strains carrying null mutations in the pertinent genes were transformed with a pkaC plasmid such that they can overexpress PKA. Since these mutant strains all sporulated efficiently when SDF-1 was added, it appears that other gene products mediate the response. However, we found that regA- mutant cells release a distinct factor, SDF-2, that rapidly induces encapsulation of test cells overexpressing pkaC. Since cells in which tagC is disrupted do not form SDF-2 and cells in which dhkA is disrupted do not respond to SDF-2, this peptide appears to use the two-component system that regulates PKA activity. SDF-2 is a small peptide released by prestalk cells in a manner dependent on TagC. It appears to act on prespore cells through the DhkA receptor to inhibit the cAMP phosphodiesterase of RegA, thereby activating PKA via cAMP. The process of induction by SDF-2 can be shown to be distinct from that by SDF-1. SDF-2 appears to stimulate prestalk cells to release additional SDF-2 by acting through a signal transduction pathway that also involves DhkA, RegA, and PKA. Based on these results we present a model for the signal transduction cascade regulating spore differentiation.

Animals↗
PubMed1991

Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10.

Human umbilical vein endothelial (HUVE) cells have been previously reported to express the genes for the A and B chains of PDGF and to secrete PDGF-related factors into culture media. Antihuman PDGF IgG affinity chromatography was used to purify PDGF-related activity from HUVE cell-conditioned media. Immunoblot analysis of the affinity-purified proteins with anti-PDGF IgG and antibodies specific for the A or B chain peptides of PDGF combined with chemotactic and mitogenic assays revealed that the major PDGF immunorelated molecule secreted by HUVE cells is a monomer of approximately 36-38 kD and that less than 10% of the purified biologically active molecules are PDGF A or B chain peptides. Screening of an HUVE cell cDNA library in the expression vector lambda gtl 1 with the anti-PDGF antibody resulted in the cloning and sequencing of a cDNA with an open reading frame encoding a 38-kD cysteine-rich secreted protein which we show to be the major PDGF-related mitogen secreted by human vascular endothelial cells. The protein has a 45% overall homology to the translation product of the v-src-induced CEF-10 mRNA from chick embryo fibroblasts. We have termed this new mitogen connective tissue growth factor.

Amino Acid Sequence↗
PubMed2004

Connective-tissue growth factor modulates WNT signalling and interacts with the WNT receptor complex.

Connective-tissue growth factor (CTGF) is a member of the CCN family of secreted proteins. CCN family members contain four characteristic domains and exhibit multiple activities: they associate with the extracellular matrix, they can mediate cell adhesion, cell migration and chemotaxis, and they can modulate the activities of peptide growth factors. Many of the effects of CTGF are thought to be mediated by binding to integrins, whereas others may be because of its recently identified ability to interact with BMP4 and TGF beta. We demonstrate, using Xenopus embryos, that CTGF also regulates signalling through the Wnt pathway, in accord with its ability to bind to the Wnt co-receptor LDL receptor-related protein 6 (LRP6). This interaction is likely to occur through the C-terminal (CT) domain of CTGF, which is distinct from the BMP- and TGF beta-interacting domain. Our results define new activities of CTGF and add to the variety of routes through which cells regulate growth factor activity in development, disease and tissue homeostasis.

Amino Acid Sequence↗