Property Summary

NCBI Gene PubMed Count 89
PubMed Score 43.36
PubTator Score 61.44

Knowledge Summary

Patent (24,606)

Expression

  Differential Expression (9)

Disease log2 FC p
psoriasis -2.100 7.9e-05
osteosarcoma -1.808 4.0e-05
juvenile dermatomyositis 1.220 5.7e-11
acute quadriplegic myopathy 1.442 9.6e-06
primary pancreatic ductal adenocarcinoma 1.098 5.4e-03
intraductal papillary-mucinous neoplasm ... 1.600 1.0e-02
Breast cancer 3.700 2.2e-02
subependymal giant cell astrocytoma -1.284 6.2e-03
ovarian cancer -2.600 4.1e-11

 GO Component (1)

Protein-protein Interaction (2)

MLP Assay (2)

AID Type Active / Inconclusive / Inactive Description
2277 screening 14 / 0 / 0 Center Based Initiative to identify novel modulators of the Retinoic acid receptor-related Orphan Receptors (ROR): luminescence-based high throughput cell-based assay to identify modulators of human nuclear receptors.
504934 other 1 / 0 / 0 Late stage assay provider results from the probe development effort to identify inverse agonists of the liver receptor homolog-1 (LRH-1; NR5A2): luminescence-based high throughput cell-based assay to identify modulators of human nuclear receptors

Gene RIF (62)

PMID Text
26884850 TAK1/TAB1 expression in non-small cell lung carcinoma tissue is significantly increased and closely associated with patient clinical prognosis.
26620228 Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings.
26617776 miR-203 represses NF-kappaB signaling via targeting TAK1 and PI3KCA and miR-203 overexpression may contribute to the COPD initiation.
26432169 DK1 inhibits the formation of the TAK1-TAB2-TRAF6 complex and leads to the inhibition of TRAF6 ubiquitination.
26334375 IFIT5 promotes SeV-induced IKK phosphorylation and NF-kappaB activation by regulating the recruitment of IKK to TAK1.
26240016 USP18 negatively regulates NF-kappaB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms.
26178291 TR4 was found to mediate the prostate cancer cells' radio-sensitivity.
26144287 TR4 expression in NSCLC samples is significantly associated with poor clinicopathological features, and TR4 plays an important role in the metastatic capacity of NSCLC cells by EMT regulation.
25980442 TR4 may increase prostate cancer metastasis and invasion via decreasing the miR-373-3p expression that resulted in the activation of the TGFbetaR2/p-Smad3 signals.
25925376 PCa patients receiving TZD treatment who have one allele TR4 deletion.
25833838 Results suggest that the testicular nuclear receptor 4 (TR4) and oncogene EZH2 signaling may play a critical role in the prostate cancer stem/progenitor cell invasion.
25704183 Helicobacter pylori induces internalization of EGFR via novel TAK1-p38-serine activation pathway which is independent of HB-EGF.
25623427 IHC staining showed higher TR4 level, more macrophage infiltration, lower TIMP-1 and stronger MMP2/MMP9 in tumor tissues.
25561507 Compound loss of function of nuclear receptors Tr2 and Tr4 leads to induction of murine embryonic beta-type globin genes.
25512613 the TAK1-NLK pathway is a novel regulator of basal or IL-1beta-triggered C/EBP activation though stabilization of ATF5
25475726 CXC195 suppresses proliferation and inflammatory response in LPS-induced human hepatocellular carcinoma cells via regulating TLR4-MyD88-TAK1-mediated NF-kappaB and MAPK pathway
25320283 Resolvin D1 attenuates the viral mimic-induced inflammatory signaling in human airway epithelial cells via TAK1.
25277189 TAK1 activates NF-kappaB signaling activity such activated TAK1/NF-kappaB signaling cascade is indispensable in promoting ovarian cancer cell growth
24975468 A role for TR4 in prostate cancer metastasis via CCL2/CCR2 signaling.
24942571 Authors demonstrate that enterovirus 71 3C interacts with TAB2 and TAK1 and suppresses cytokine expression via cleavage of the TAK1 complex proteins.
24912525 Knockdown of endogenous TAK1 significantly attenuated the ability of Vpr to activate NF-kappaB and AP-1.
24907344 TR4 binding with keto-MA features a unique association of host nuclear receptor with a bacterial lipid and adds to the presently known ligand repertoire beyond dietary lipids.
24811540 study reveals that the TR4 regulatory network is far more complex than previously appreciated and that TR4 regulates basic, essential biological processes during the terminal differentiation of human erythroid cells.
24801688 TAK1 is a key regulator of receptor crosstalk between BCR and TLR9.
24728340 our findings describe a TAK1-dependent, beta-catenin- and Sp1-mediated signaling cascade activated downstream of TGF-beta which regulates WNT-5A induction.
24583925 TR4 nuclear receptor functions as a tumor suppressor for prostate tumorigenesis via modulation of DNA damage/repair system.
24565101 miR-26b suppresses NF-kappaB signaling and sensitizes hepatocellular carcinoma cells to doxorubicin-induced apoptosis by inhibiting the expression of TAK1 and TAB3.
24418622 We provide evidence for an intimate mutual control of the IKK complex by mitogen-activated protein kinase kinase kinase 3 (MEKK3) and transforming growth factor beta activated kinase 1 (TAK1).
24337384 Small interfering RNA-mediated silencing of TRAF6 and TAK1.
24082073 TAK1 regulates H. pylori-mediated early JNK activation and cytokine production.
24028082 Findings reveal the role of TAK1 in thermoresistance and show that the mediation is independent of NF-kappaB phosphorylation but is dependent on TNFAIP3 and IL-8 induction.
23770285 These results reveal Sef-S actives Lys63-linked TAK1 polyubiquitination on lysine 209, induces TAK1-mediated JNK and p38 activation and also results apoptosis in 293T cells.
23700229 The results provide a proof-of-concept that TAK1 inhibition significantly increases the sensitivity of neuroblastoma cells to chemotherapy-induced cell-death.
23653479 TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation.
23609451 TR4-Oct4-IL1Ra axis may play a critical role in the development of chemoresistance in the PCa stem/progenitor cells.
23463759 Mice that lack the ortholog of this gene display severe spinal curvature, subfertility, premature aging, and prostatic intraepithelial neoplasia (PIN) development.
22981905 Lys63-linked TAK1 polyubiquitination at Lys-158 is required for Dox-induced NF-kappaB activation.
22851693 Beta-TrCP deficiency abolished the translocation TAK1-TRAF6 complex from the membrane to the cytosol, resulting in a diminishment of the IL-1-induced TAK1-dependent pathway.
22643835 PINK1 positively regulates two key molecules, TRAF6 and TAK1, in the IL-1beta-mediated signaling pathway, consequently up-regulating their downstream inflammatory events
22641218 Celastrol highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-beta-NF-kappaB signal pathway
22544925 Mycobacterium tuberculosis interacts with macrophage lipids and human host testicular receptor (TR)4 to ensure survival of the pathogen by modulating macrophage function.
21980489 the protein associates with TGF-beta receptors and components of the TRAF6-TAK1 signaling module
21918225 Testicular nuclear receptor 4 (TR4) regulates UV light-induced responses via Cockayne syndrome B protein-mediated transcription-coupled DNA repair
21915030 The purpose of the study was to investigate the potential contribution of HPK1, MEKK1, TAK1, p-MKK4 to the development of extramammary Paget disease
21835421 These results demonstrated the role of TAK1 as an important upstream signaling molecule regulating RSV-induced NF-kappaB and AP-1 activation.
21331078 Results demonstrate that USP4 serves as a critical control to downregulate TNFalpha-induced NF-kappaB activation through deubiquitinating TAK1.
21126370 TR4 binding at a subset of sites is facilitated through the ETS transcription factor ELK4.
21068381 TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.
20604713 COX-2 gene expression and prostaglandin (PG)E2 release are specific outcomes of collagen II signaling, and both depend on TAK1 mediation in primary human chondrocytes.
20393820 TAK1 is an important transcriptional modulator of cerebellar development and neurodevelopmentally regulated behavior.
20379614 Clinical trial of gene-disease association and gene-environment interaction. (HuGE Navigator)
20200282 Our data establish the central role of TAK1 in controlling nuclear and cytoplasmic signaling cascades in primary neutrophils
20164171 the ADAP CARMA1 binding site is required for IKK gamma ubiquitination; both TAK1 and CARMA1 binding sites are required for IkappaB alpha phosphorylation and degradation and NF-kappaB nuclear translocation
19955181 Activation of IRF3 and IRF3-dependent gene expressions was dependent on TAK1 and TANK-binding kinase 1 (TBK1).
19859911 Human testicular orphan receptor 4 enhances thyroid hormone receptor signaling.
19618297 The binding activity of C/EBPs to the TR4 promoter is increased in response to cAMP treatment.
18977241 Observational study of gene-disease association. (HuGE Navigator)
17601350 Observational study of gene-disease association. (HuGE Navigator)
12615366 TR2 and TR4 can have distinct functions. Existence of differential and bi-directional regulation between PPAR alpha and TR2/TR4. Possible roles in PPAR alpha signaling pathway in human keratinocytes.
12522137 TR4 can serve as a negative modulator in the transcriptional regulation of HBV core gene expression
12093744 DRED is a 540 kDa complex containing the nuclear orphan receptors TR2 and TR4, which form a heterodimer that binds to the epsilon and gamma globin promoter DR1 sites. TR2 & 4 mRNAs are expressed at all stages of murine and human erythropoiesis.
11844790 role in modulating estrogen receptor-mediated trans-activation

AA Sequence

MTSPSPRIQIISTDSAVASPQRIQIVTDQQTGQKIQIVTAVDASGSPKQQFILTSPDGAGTGKVILASPE      1 - 70
TSSAKQLIFTTSDNLVPGRIQIVTDSASVERLLGKTDVQRPQVVEYCVVCGDKASGRHYGAVSCEGCKGF     71 - 140
FKRSVRKNLTYSCRSNQDCIINKHHRNRCQFCRLKKCLEMGMKMESVQSERKPFDVQREKPSNCAASTEK    141 - 210
IYIRKDLRSPLIATPTFVADKDGARQTGLLDPGMLVNIQQPLIREDGTVLLATDSKAETSQGALGTLANV    211 - 280
VTSLANLSESLNNGDTSEIQPEDQSASEITRAFDTLAKALNTTDSSSSPSLADGIDTSGGGSIHVISRDQ    281 - 350
STPIIEVEGPLLSDTHVTFKLTMPSPMPEYLNVHYICESASRLLFLSMHWARSIPAFQALGQDCNTSLVR    351 - 420
ACWNELFTLGLAQCAQVMSLSTILAAIVNHLQNSIQEDKLSGDRIKQVMEHIWKLQEFCNSMAKLDIDGY    421 - 490
EYAYLKAIVLFSPDHPGLTSTSQIEKFQEKAQMELQDYVQKTYSEDTYRLARILVRLPALRLMSSNITEE    491 - 560
LFFTGLIGNVSIDSIIPYILKMETAEYNGQITGASL                                      561 - 596
//

Text Mined References (101)

PMID Year Title
26884850 2015 Expression of TAK1/TAB1 expression in non-small cell lung carcinoma and adjacent normal tissues and their clinical significance.
26620228 2016 LYATK1 potently inhibits LPS-mediated pro-inflammatory response.
26617776 2015 Ectopic expressed miR-203 contributes to chronic obstructive pulmonary disease via targeting TAK1 and PIK3CA.
26432169 2015 Phosphoinositide-dependent kinase-1 inhibits TRAF6 ubiquitination by interrupting the formation of TAK1-TAB2 complex in TLR4 signaling.
26334375 2015 IFIT5 positively regulates NF-?B signaling through synergizing the recruitment of I?B kinase (IKK) to TGF-?-activated kinase 1 (TAK1).
26240016 2015 USP18 negatively regulates NF-?B signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms.
26178291 2015 Testicular orphan nuclear receptor 4 is associated with the radio-sensitivity of prostate cancer.
26144287 2015 Testicular orphan receptor 4 (TR4) is a marker for metastasis and poor prognosis in non-small cell lung cancer that drives the EMT phenotype.
25980442 2015 TR4 nuclear receptor increases prostate cancer invasion via decreasing the miR-373-3p expression to alter TGF?R2/p-Smad3 signals.
25925376 2015 The Differential Effects of Anti-Diabetic Thiazolidinedione on Prostate Cancer Progression Are Linked to the TR4 Nuclear Receptor Expression Status.
25833838 2015 TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression.
25704183 2015 Helicobacter pylori Induces Serine Phosphorylation of EGFR via Novel TAK1-p38 Activation Pathway in an HB-EGF-Independent Manner.
25623427 2015 Targeting TR4 nuclear receptor suppresses prostate cancer invasion via reduction of infiltrating macrophages with alteration of the TIMP-1/MMP2/MMP9 signals.
25561507 2015 Compound loss of function of nuclear receptors Tr2 and Tr4 leads to induction of murine embryonic ?-type globin genes.
25512613 2015 Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the interleukin-1?-stimulated C/EBP signaling pathway.
25475726 2015 CXC195 suppresses proliferation and inflammatory response in LPS-induced human hepatocellular carcinoma cells via regulating TLR4-MyD88-TAK1-mediated NF-?B and MAPK pathway.
25320283 2014 Resolvin D1 attenuates polyinosinic-polycytidylic acid-induced inflammatory signaling in human airway epithelial cells via TAK1.
25277189 2014 Elevated TAK1 augments tumor growth and metastatic capacities of ovarian cancer cells through activation of NF-?B signaling.
24975468 2015 TR4 nuclear receptor promotes prostate cancer metastasis via upregulation of CCL2/CCR2 signaling.
24942571 2014 Enterovirus 71 3C inhibits cytokine expression through cleavage of the TAK1/TAB1/TAB2/TAB3 complex.
24912525 2014 HIV-1 Vpr stimulates NF-?B and AP-1 signaling by activating TAK1.
24907344 2014 Mycobacterium tuberculosis keto-mycolic acid and macrophage nuclear receptor TR4 modulate foamy biogenesis in granulomas: a case of a heterologous and noncanonical ligand-receptor pair.
24811540 2014 Biased, non-equivalent gene-proximal and -distal binding motifs of orphan nuclear receptor TR4 in primary human erythroid cells.
24801688 2014 TGF? activated kinase 1 (TAK1) at the crossroad of B cell receptor and Toll-like receptor 9 signaling pathways in human B cells.
24728340 2014 TGF-?-activated kinase 1 (TAK1) signaling regulates TGF-?-induced WNT-5A expression in airway smooth muscle cells via Sp1 and ?-catenin.
24583925 2014 TR4 nuclear receptor functions as a tumor suppressor for prostate tumorigenesis via modulation of DNA damage/repair system.
24565101 2014 MicroRNA-26b suppresses the NF-?B signaling and enhances the chemosensitivity of hepatocellular carcinoma cells by targeting TAK1 and TAB3.
24418622 2014 MEKK3 and TAK1 synergize to activate IKK complex in Helicobacter pylori infection.
24337384 2014 TNFR-associated factor 6 and TGF-?-activated kinase 1 control signals for a senescence response by an endosomal NK cell receptor.
24082073 2013 Differential roles of ASK1 and TAK1 in Helicobacter pylori-induced cellular responses.
24028082 2013 TAK1 promotes cell survival by TNFAIP3 and IL-8 dependent and NF-?B independent pathway in HeLa cells exposed to heat stress.
23940728 2013 AMD-associated genes encoding stress-activated MAPK pathway constituents are identified by interval-based enrichment analysis.
23770285 2013 Activation of TAK1 by Sef-S induces apoptosis in 293T cells.
23700229 2013 TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy.
23653479 2013 Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease.
23609451 2013 Increased chemosensitivity via targeting testicular nuclear receptor 4 (TR4)-Oct4-interleukin 1 receptor antagonist (IL1Ra) axis in prostate cancer CD133+ stem/progenitor cells to battle prostate cancer.
23463759 2013 Recent advances in the study of testicular nuclear receptor 4.
23416702 2013 Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction.
23186163 2013 Toward a comprehensive characterization of a human cancer cell phosphoproteome.
22981905 2013 TAK1 ubiquitination regulates doxorubicin-induced NF-?B activation.
22851693 2012 ?-TrCP-mediated IRAK1 degradation releases TAK1-TRAF6 from the membrane to the cytosol for TAK1-dependent NF-?B activation.
22672233 2012 NLRP10 enhances Shigella-induced pro-inflammatory responses.
22643835 2012 PINK1 stimulates interleukin-1?-mediated inflammatory signaling via the positive regulation of TRAF6 and TAK1.
22641218 2013 TGF-? and NF-?B signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers.
22544925 2012 Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPAR? and TR4 for survival.
22488850 2012 Genome-wide search for replicable risk gene regions in alcohol and nicotine co-dependence.
22486638 2012 Evaluating the Cornell Scale for Depression in Dementia as a proxy measure in nursing home residents with and without dementia.
22020285 2011 Image-based genome-wide siRNA screen identifies selective autophagy factors.
21980489 2011 TTRAP is a novel component of the non-canonical TRAF6-TAK1 TGF-? signaling pathway.
21918225 2011 Testicular nuclear receptor 4 (TR4) regulates UV light-induced responses via Cockayne syndrome B protein-mediated transcription-coupled DNA repair.
21915030 2011 Hematopoietic progenitor kinase 1, mitogen-activated protein/extracellular signal-related protein kinase kinase kinase 1, and phosphomitogen-activated protein kinase kinase 4 are overexpressed in extramammary Paget disease.
21835421 2011 TAK1 regulates NF-?B and AP-1 activation in airway epithelial cells following RSV infection.
21670149 2011 Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic ?-type globin promoters in differentiated adult erythroid cells.
21331078 2011 USP4 targets TAK1 to downregulate TNF?-induced NF-?B activation.
21126370 2010 Genome-wide binding of the orphan nuclear receptor TR4 suggests its general role in fundamental biological processes.
21068381 2011 The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor.
20604713 2010 TAK1 mediates the collagen-II-dependent induction of the COX-2 gene and PGE2 release in primary human chondrocytes.
20393820 2010 Altered cerebellar development in nuclear receptor TAK1/ TR4 null mice is associated with deficits in GLAST(+) glia, alterations in social behavior, motor learning, startle reactivity, and microglia.
20379614 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.
20200282 2010 Constitutive association of TGF-beta-activated kinase 1 with the IkappaB kinase complex in the nucleus and cytoplasm of human neutrophils and its impact on downstream processes.
20164171 2010 NF-kappaB activation in T cells requires discrete control of IkappaB kinase alpha/beta (IKKalpha/beta) phosphorylation and IKKgamma ubiquitination by the ADAP adapter protein.
20068231 2010 Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.
19955181 2010 Human T cell lymphotropic virus 1 manipulates interferon regulatory signals by controlling the TAK1-IRF3 and IRF4 pathways.
19859911 2010 Human testicular orphan receptor 4 enhances thyroid hormone receptor signaling.
19690332 2009 Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.
19618297 2009 Activation of TR4 orphan nuclear receptor gene promoter by cAMP/PKA and C/EBP signaling.
18977241 2008 Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey.
18669648 2008 A quantitative atlas of mitotic phosphorylation.
18619963 2008 DNA-binding profiling of human hormone nuclear receptors via fluorescence correlation spectroscopy in a cell-free system.
18388194 2008 Oxidative stress stimulates testicular orphan receptor 4 through forkhead transcription factor forkhead box O3a.
18029348 2008 Toward a confocal subcellular atlas of the human proteome.
17974920 2007 The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription.
17601350 2007 A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition.
16887930 2006 Modulation of testicular receptor 4 activity by mitogen-activated protein kinase-mediated phosphorylation.
16751776 2006 A germline-specific class of small RNAs binds mammalian Piwi proteins.
16641997 2006 The DNA sequence, annotation and analysis of human chromosome 3.
15381082 2004 Modulation of the retinoic acid-induced cell apoptosis and differentiation by the human TR4 orphan nuclear receptor.
15302918 2004 TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4.
15193450 2004 Gene silencing by nuclear orphan receptors.
14743216 2004 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.
14702039 2004 Complete sequencing and characterization of 21,243 full-length human cDNAs.
14633987 2003 Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling.
12615366 2003 Differential and bi-directional regulation between TR2/TR4 orphan nuclear receptors and a specific ligand mediated-peroxisome proliferator-activated receptor alpha in human HaCaT keratinocytes.
12547194 2003 TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway.
12522137 2003 Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4.
12486131 2003 Identification of a novel testicular orphan receptor-4 (TR4)-associated protein as repressor for the selective suppression of TR4-mediated transactivation.
12477932 2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.
12361719 2002 Recent advances in the TR2 and TR4 orphan receptors of the nuclear receptor superfamily.
12093744 2002 An embryonic/fetal beta-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer.
11844790 2002 Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells.
11585904 2001 Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation.
10644740 2000 Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor.
10611280 1999 Convergence of two repressors through heterodimer formation of androgen receptor and testicular orphan receptor-4: a unique signaling pathway in the steroid receptor superfamily.
10347174 1999 Differential regulation of direct repeat 3 vitamin D3 and direct repeat 4 thyroid hormone signaling pathways by the human TR4 orphan receptor.
9737983 1998 A novel nuclear receptor heterodimerization pathway mediated by orphan receptors TR2 and TR4.
9556573 1998 Regulation of peroxisome proliferator-activated receptor alpha-induced transactivation by the nuclear orphan receptor TAK1/TR4.
9006963 1997 Induction of the intronic enhancer of the human ciliary neurotrophic factor receptor (CNTFRalpha) gene by the TR4 orphan receptor. A member of steroid receptor superfamily.
8661150 1996 New variants of the human and rat nuclear hormone receptor, TR4: expression and chromosomal localization of the human gene.
8016112 1994 Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily.
7779113 1995 The orphan receptor TAK1 acts as a repressor of RAR-, RXR- and T3R-mediated signaling pathways.
7708055 1994 TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily.