STRINGSTRING
SFRP1 SFRP1 HDAC7 HDAC7 VEGFC VEGFC TWIST2 TWIST2 NOTCH1 NOTCH1 GREM1 GREM1 RIOX1 RIOX1 GDF10 GDF10 TOB1 TOB1 RANBP3L RANBP3L SEMA4D SEMA4D TMEM64 TMEM64 CITED1 CITED1 TNF TNF AREG AREG UCMA UCMA SKI SKI RORB RORB BAMBI BAMBI ID3 ID3 SUFU SUFU HAND2 HAND2 NBR1 NBR1 OSTN OSTN MEN1 MEN1 SMAD3 SMAD3 PTCH1 PTCH1 NOG NOG AXIN2 AXIN2 LRP5 LRP5 SMAD6 SMAD6 PPARG PPARG NOCT NOCT CRIM1 CRIM1 LIMD1 LIMD1 CDK6 CDK6 TWSG1 TWSG1 TRPM4 TRPM4 SOX9 SOX9 TNFAIP6 TNFAIP6 TWIST1 TWIST1 TNN TNN FGF23 FGF23 IGFBP5 IGFBP5 HOXA2 HOXA2 CHRD CHRD
Nodes:
Network nodes represent proteins
splice isoforms or post-translational modifications are collapsed, i.e. each node represents all the proteins produced by a single, protein-coding gene locus.
Node Color
colored nodes:
query proteins and first shell of interactors
white nodes:
second shell of interactors
Node Content
empty nodes:
proteins of unknown 3D structure
filled nodes:
a 3D structure is known or predicted
Edges:
Edges represent protein-protein associations
associations are meant to be specific and meaningful, i.e. proteins jointly contribute to a shared function; this does not necessarily mean they are physically binding to each other.
Known Interactions
from curated databases
experimentally determined
Predicted Interactions
gene neighborhood
gene fusions
gene co-occurrence
Others
textmining
co-expression
protein homology
Your Input:
SFRP1Secreted frizzled-related protein 1; Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts. They have a role in regulating cell growth and differentiation in specific cell types. SFRP1 decreases intracellular beta-catenin levels (By similarity). Has antiproliferative effects on vascular cells, in vitro and in vivo, and can induce, in vivo, an angiogenic response. In vascular cell cycle, delays the G1 phase and entry into the S phase (By similarity). In kidney development, inhibits tubule formation and bud growth in metane [...] (314 aa)
HDAC7Histone deacetylase 7; Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression [...] (991 aa)
VEGFCVascular endothelial growth factor C; Growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels. May function in angiogenesis of the venous and lymphatic vascular systems during embryogenesis, and also in the maintenance of differentiated lymphatic endothelium in adults. Binds and activates KDR/VEGFR2 and FLT4/VEGFR3 receptors. (419 aa)
TWIST2Twist-related protein 2; Binds to the E-box consensus sequence 5'-CANNTG-3' as a heterodimer and inhibits transcriptional activation by MYOD1, MYOG, MEF2A and MEF2C. Also represses expression of proinflammatory cytokines such as TNFA and IL1B. Involved in postnatal glycogen storage and energy metabolism (By similarity). Inhibits the premature or ectopic differentiation of preosteoblast cells during osteogenesis, possibly by changing the internal signal transduction response of osteoblasts to external growth factors. (160 aa)
NOTCH1Neurogenic locus notch homolog protein 1; Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the [...] (2555 aa)
GREM1Gremlin-1; Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop. Down-regulates the BMP4 signaling in a dose-dependent manner (By similarity). Antagonist of BMP2; inhibits BMP2-mediated differentiation of osteoblasts (in vitro). Acts as inhibitor of monocyte chemotaxis. Can inhibit the growth or viability of normal cells but not transformed cells when is overexpressed (By similarity). Belongs to the DAN family. (184 aa)
RIOX1Ribosomal oxygenase 1; Oxygenase that can act as both a histone lysine demethylase and a ribosomal histidine hydroxylase. Specifically demethylates 'Lys- 4' (H3K4me) and 'Lys-36' (H3K36me) of histone H3, thereby playing a central role in histone code. Preferentially demethylates trimethylated H3 'Lys-4' (H3K4me3) and monomethylated H3 'Lys-4' (H3K4me1) residues, while it has weaker activity for dimethylated H3 'Lys-36' (H3K36me2). Also catalyzes the hydroxylation of 60S ribosomal protein L8 on 'His- 216'. Acts as a regulator of osteoblast differentiation via its interaction with SP7/OS [...] (641 aa)
GDF10Growth/differentiation factor 10; Growth factor involved in osteogenesis and adipogenesis. Plays an inhibitory role in the process of osteoblast differentiation via SMAD2/3 pathway. Plays an inhibitory role in the process of adipogenesis; Belongs to the TGF-beta family. (478 aa)
TOB1Protein Tob1; Anti-proliferative protein; the function is mediated by association with deadenylase subunits of the CCR4-NOT complex. Mediates CPEB3-accelerated mRNA deadenylation by binding to CPEB3 and recruiting CNOT7 which leads to target mRNA deadenylation and decay. Belongs to the BTG family. (345 aa)
RANBP3LRan-binding protein 3-like; Nuclear export factor for BMP-specific SMAD1/5/8 that plays a critical role in terminating BMP signaling and regulating mesenchymal stem cell differentiation by blocking osteoblast differentiation to promote myogenic differention. Directly recognizes dephosphorylated SMAD1/5/8 and mediates their nuclear export in a Ran-dependent manner. (490 aa)
SEMA4DSemaphorin-4D; Cell surface receptor for PLXNB1 and PLXNB2 that plays an important role in cell-cell signaling. Regulates GABAergic synapse development (By similarity). Promotes the development of inhibitory synapses in a PLXNB1-dependent manner (By similarity). Modulates the complexity and arborization of developing neurites in hippocampal neurons by activating PLXNB1 and interaction with PLXNB1 mediates activation of RHOA. Promotes the migration of cerebellar granule cells. Plays a role in the immune system; induces B-cells to aggregate and improves their viability (in vitro). Induce [...] (862 aa)
TMEM64Transmembrane protein 64; Positively regulates TNFSF11-induced osteoclast differentiation. Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with SERCA2 which is critical for the TNFSF11-induced CREB1 activation and mitochondrial ROS generation necessary for proper osteoclast generation. Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca (2+) spiking for activation of NFATC1 and production of mitochondrial ROS, thereby triggering Ca (2+) signaling cascades that promote osteoclast differentiation and activation. Negatively regulates [...] (380 aa)
CITED1Cbp/p300-interacting transactivator 1; Transcriptional coactivator of the p300/CBP-mediated transcription complex. Enhances SMAD-mediated transcription by strengthening the functional link between the DNA-binding SMAD transcription factors and the p300/CBP transcription coactivator complex. Stimulates estrogen-dependent transactivation activity mediated by estrogen receptors signaling; stabilizes the interaction of estrogen receptor ESR1 and histone acetyltransferase EP300. Positively regulates TGF-beta signaling through its association with the SMAD/p300/CBP-mediated transcriptional c [...] (219 aa)
TNFTumor necrosis factor, membrane form; Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T- cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 [...] (233 aa)
AREGAmphiregulin; Ligand of the EGF receptor/EGFR. Autocrine growth factor as well as a mitogen for a broad range of target cells including astrocytes, Schwann cells and fibroblasts; Belongs to the amphiregulin family. (252 aa)
UCMAUnique cartilage matrix-associated protein C-terminal fragment; May be involved in the negative control of osteogenic differentiation of osteochondrogenic precursor cells in peripheral zones of fetal cartilage and at the cartilage-bone interface. (138 aa)
SKISki oncogene; May play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage. Functions as a repressor of TGF-beta signaling. Belongs to the SKI family. (728 aa)
RORBNuclear receptor ROR-beta; Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Considered to have intrinsic transcriptional activity, have some natural ligands such as all-trans retinoic acid (ATRA) and other retinoids which act as inverse agonists repressing the transcriptional activity. Required for normal postnatal development of rod and cone photoreceptor cells. Modulates rod photoreceptors differentiation at least by inducing the transcription factor NRL-mediated p [...] (459 aa)
BAMBIBMP and activin membrane-bound inhibitor homolog; Negatively regulates TGF-beta signaling; Belongs to the BAMBI family. (260 aa)
ID3DNA-binding protein inhibitor ID-3; Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity. Implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation. Involved in myogenesis by inhibiting skeletal muscle and cardiac myocyte differentiation and promoting muscle precursor cells proliferation. Inhibits the [...] (119 aa)
SUFUSuppressor of fused homolog; Negative regulator in the hedgehog/smoothened signaling pathway. Down-regulates GLI1-mediated transactivation of target genes. Down-regulates GLI2-mediated transactivation of target genes. Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1 to BTRC and thereby targeting GLI1 to degradation by the proteasome. Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein. Negative regulator of beta-catenin signaling (By similarity). Regulates the formation of eit [...] (484 aa)
HAND2Heart- and neural crest derivatives-expressed protein 2; Essential for cardiac morphogenesis, particularly for the formation of the right ventricle and of the aortic arch arteries. Required for vascular development and regulation of angiogenesis, possibly through a VEGF signaling pathway. Plays also an important role in limb development, particularly in the establishment of anterior- posterior polarization, acting as an upstream regulator of sonic hedgehog (SHH) induction in the limb bud. Is involved in the development of branchial arches, which give rise to unique structures in the he [...] (217 aa)
NBR1Next to BRCA1 gene 1 protein; Acts probably as a receptor for selective autophagosomal degradation of ubiquitinated targets. (966 aa)
OSTNProcessed Osteocrin; Hormone that acts as a regulator of dendritic growth in the developing cerebral cortex in response to sensory experience. Induced in the brain following membrane depolarization and inhibits dendritic branching in neurons of the developing cortex. Probably acts by binding to natriuretic peptide receptor NPR3/NPR-C, thereby preventing binding between NPR3/NPR-C and natriuretic peptides, leading to increase cGMP production (By similarity); Belongs to the Osteocrin family. (133 aa)
MEN1Menin; Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3 (H3K4). Functions as a transcriptional regulator. Binds to the TERT promoter and represses telomerase expression. Plays a role in TGFB1-mediated inhibition of cell-proliferation, possibly regulating SMAD3 transcriptional activity. Represses JUND-mediated transcriptional activation on AP1 sites, as well as that mediated by NFKB subunit RELA. Positively regulates HOXC8 and HOXC6 gene expression. May be involved in normal hematopoiesis through the [...] (615 aa)
SMAD3Mothers against decapentaplegic homolog 3; Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP- 1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and m [...] (425 aa)
PTCH1Protein patched homolog 1; Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis. Belongs to the patched family. (1447 aa)
NOGNoggin; Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite. Essential for cartilage morphogenesis and joint formation. Inhibits chondrocyte differentiation through its interaction with GDF5 and, probably, GDF6. (232 aa)
AXIN2Axin-2; Inhibitor of the Wnt signaling pathway. Down-regulates beta- catenin. Probably facilitate the phosphorylation of beta-catenin and APC by GSK3B. (843 aa)
LRP5Low-density lipoprotein receptor-related protein 5; Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins. Activates the canonical Wnt signaling pathway that controls cell fate determination and self-renewal during embryonic development and adult tissue regeneration. In particular, may play an important role in the development of the posterior patterning of the epiblast during gastrulation (By similarity). During bone development, regulates osteoblast proliferation and differentiation thus determining bone [...] (1615 aa)
SMAD6Mothers against decapentaplegic homolog 6; Acts as a mediator of TGF-beta and BMP antiflammatory activity. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF- kappa-B-mediated expression of proinflammatory genes. May block the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor- activated SMAD1-binding. Binds to regulatory elements in target promoter regions. (496 aa)
PPARGPeroxisome proliferator-activated receptor gamma; Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut ho [...] (505 aa)
NOCTNocturnin; Phosphatase which catalyzes the conversion of NADP(+) to NAD(+) and of NADPH to NADH. Shows a small preference for NADPH over NADP(+). Represses translation and promotes degradation of target mRNA molecules. Plays an important role in post-transcriptional regulation of metabolic genes under circadian control (By similarity). Exerts a rhythmic post- transcriptional control of genes necessary for metabolic functions including nutrient absorption, glucose/insulin sensitivity, lipid metabolism, adipogenesis, inflammation and osteogenesis (By similarity). Plays an important role [...] (431 aa)
CRIM1Processed cysteine-rich motor neuron 1 protein; May play a role in CNS development by interacting with growth factors implicated in motor neuron differentiation and survival. May play a role in capillary formation and maintenance during angiogenesis. Modulates BMP activity by affecting its processing and delivery to the cell surface. (1036 aa)
LIMD1LIM domain-containing protein 1; Adapter or scaffold protein which participates in the assembly of numerous protein complexes and is involved in several cellular processes such as cell fate determination, cytoskeletal organization, repression of gene transcription, cell-cell adhesion, cell differentiation, proliferation and migration. Positively regulates microRNA (miRNA)-mediated gene silencing and is essential for P-body formation and integrity. Acts as a hypoxic regulator by bridging an association between the prolyl hydroxylases and VHL enabling efficient degradation of HIF1A. Acts [...] (676 aa)
CDK6Cyclin-dependent kinase 6; Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cel [...] (326 aa)
TWSG1Twisted gastrulation protein homolog 1; May be involved in dorsoventral axis formation. Seems to antagonize BMP signaling by forming ternary complexes with CHRD and BMPs, thereby preventing BMPs from binding to their receptors. In addition to the anti-BMP function, also has pro-BMP activity, partly mediated by cleavage and degradation of CHRD, which releases BMPs from ternary complexes. May be an important modulator of BMP-regulated cartilage development and chondrocyte differentiation. May play a role in thymocyte development (By similarity); Belongs to the twisted gastrulation protei [...] (223 aa)
TRPM4Transient receptor potential cation channel subfamily M member 4; Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization. While it is activated by increase in intracellular Ca(2+), it is impermeable to it. Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating [...] (1214 aa)
SOX9Transcription factor SOX-9; Transcriptional regulator that plays a role in chondrocytes differentiation and skeletal development. Binds to the COL2A1 promoter and activates COL2A1 expression, as part of a complex with ZNF219 (By similarity). (509 aa)
TNFAIP6Tumor necrosis factor-inducible gene 6 protein; Possibly involved in cell-cell and cell-matrix interactions during inflammation and tumorigenesis. (277 aa)
TWIST1Twist-related protein 1; Acts as a transcriptional regulator. Inhibits myogenesis by sequestrating E proteins, inhibiting trans-activation by MEF2, and inhibiting DNA-binding by MYOD1 through physical interaction. This interaction probably involves the basic domains of both proteins. Also represses expression of proinflammatory cytokines such as TNFA and IL1B. Regulates cranial suture patterning and fusion. Activates transcription as a heterodimer with E proteins. Regulates gene expression differentially, depending on dimer composition. Homodimers induce expression of FGFR2 and POSTN w [...] (202 aa)
TNNTenascin-N; Extracellular matrix protein that seems to be a ligand for ITGA8:ITGB1, ITGAV:ITGB1 and ITGA4:ITGB1 (By similarity). Involved in neurite outgrowth and cell migration in hippocampal explants (By similarity). During endochondral bone formation, inhibits proliferation and differentiation of proteoblasts mediated by canonical WNT signaling (By similarity). In tumors, stimulates angiogenesis by elongation, migration and sprouting of endothelial cells. Expressed in most mammary tumors, may facilitate tumorigenesis by supporting the migratory behavior of breast cancer cells. ECO:0 [...] (1299 aa)
FGF23Fibroblast growth factor 23 C-terminal peptide; Regulator of phosphate homeostasis. Inhibits renal tubular phosphate transport by reducing SLC34A1 levels. Upregulates EGR1 expression in the presence of KL (By similarity). Acts directly on the parathyroid to decrease PTH secretion (By similarity). Regulator of vitamin-D metabolism. Negatively regulates osteoblast differentiation and matrix mineralization. (251 aa)
IGFBP5Insulin-like growth factor-binding protein 5; IGF-binding proteins prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cell culture. They alter the interaction of IGFs with their cell surface receptors. (272 aa)
HOXA2Homeobox protein Hox-A2; Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis; Belongs to the Antp homeobox family. Proboscipedia subfamily. (376 aa)
CHRDChordin; Dorsalizing factor. Key developmental protein that dorsalizes early vertebrate embryonic tissues by binding to ventralizing TGF-beta family bone morphogenetic proteins (BMPs) and sequestering them in latent complexes (By similarity); Belongs to the chordin family. (955 aa)
Your Current Organism:
Homo sapiens
NCBI taxonomy Id: 9606
Other names: H. sapiens, human, man
Server load: low (22%) [HD]
STRING is a Core Data Resource as designated by Global Biodata Coalition and ELIXIR.