# HISTORY 07 May 2016: Updated by: TOUCHUP-v1.18 14 Mar 2016: Updated by: TOUCHUP-v1.14 24 Mar 2016: Updated by: TOUCHUP-v1.15 # molecular_function 20100903: Eukaryota_PTN000090250 has function GTPase activator activity (GO:0005096) 20100903: Deuterostomia_PTN000090568 has function protein kinase binding (GO:0019901) 20100903: Deuterostomia_PTN000090568 has function armadillo repeat domain binding (GO:0070016) 20100903: Deuterostomia_PTN000090568 has function beta-catenin binding (GO:0008013) # cellular_component 20100903: Eukaryota_PTN000090250 is found in cytoplasm (GO:0005737) 20100903: Eukaryota_PTN000090250 is found in plasma membrane (GO:0005886) 20100903: Deuterostomia_PTN000090568 is found in postsynaptic density (GO:0014069) 20100903: Deuterostomia_PTN000090568 is found in cytoplasmic microtubule (GO:0005881) 20100903: Deuterostomia_PTN000090568 is found in beta-catenin destruction complex (GO:0030877) 20100903: Deuterostomia_PTN000090568 is found in cell cortex (GO:0005938) 20100903: Deuterostomia_PTN000090568 is found in cytoplasmic, membrane-bounded vesicle (GO:0016023) # biological_process 20100903: Deuterostomia_PTN000090568 participates in regulation of transcription, DNA-templated (GO:0006355) 20100903: Deuterostomia_PTN000090568 participates in dorsal/ventral axis specification (GO:0009950) 20100903: Deuterostomia_PTN000090568 participates in cell death (GO:0008219) 20100903: Deuterostomia_PTN000090568 participates in Wnt signaling pathway involved in somitogenesis (GO:0090244) 20100903: Deuterostomia_PTN000090568 participates in cellular response to organic cyclic compound (GO:0071407) 20100903: Deuterostomia_PTN000090568 participates in regulation of catenin import into nucleus (GO:0035412) 20100903: Deuterostomia_PTN000090568 participates in cell differentiation (GO:0030154) 20100903: Deuterostomia_PTN000090568 participates in negative regulation of canonical Wnt signaling pathway (GO:0090090) 20100903: Euteleostomi_PTN000090570 participates in negative regulation of osteoblast differentiation (GO:0045668) 20100903: Euteleostomi_PTN000090570 participates in intramembranous ossification (GO:0001957) 20100903: Euteleostomi_PTN000090599 participates in olfactory placode formation (GO:0030910) 20100903: Euteleostomi_PTN000090599 participates in negative regulation of fat cell differentiation (GO:0045599) 20100903: Euteleostomi_PTN000090599 participates in negative regulation of transcription elongation from RNA polymerase II promoter (GO:0034244) 20100903: Euteleostomi_PTN000090599 participates in canonical Wnt signaling pathway involved in neural plate anterior/posterior pattern formation (GO:0060823) 20100903: Euteleostomi_PTN000090599 participates in Wnt-activated signaling pathway involved in forebrain neuron fate commitment (GO:0021881) 20100903: Euteleostomi_PTN000090599 participates in activation of JUN kinase activity (GO:0007257) 20100903: Euteleostomi_PTN000090599 participates in muscle cell development (GO:0055001) 20100903: Euteleostomi_PTN000090599 participates in forebrain anterior/posterior pattern specification (GO:0021797) 20100903: Euteleostomi_PTN000090599 participates in embryonic eye morphogenesis (GO:0048048) 20100903: Euteleostomi_PTN000090599 participates in embryonic skeletal joint morphogenesis (GO:0060272) 20100903: Euteleostomi_PTN000090599 participates in axial mesoderm formation (GO:0048320) 20100903: Euteleostomi_PTN000090599 participates in determination of left/right symmetry (GO:0007368) 20100903: Euteleostomi_PTN000090599 participates in optic placode formation (GO:0001743) 20100903: Euteleostomi_PTN000090599 participates in cytoplasmic microtubule organization (GO:0031122) # WARNINGS - THE FOLLOWING HAVE BEEN REMOVED FOR THE REASONS NOTED # NOTES Description of phylogeny This family consists of 6 metazoan clades with the following outgroups, starting with the most distant: TAIR RGS1 dicty/entamoeba clade of uncharacterized proteins fungal clade, incl. yeast RGS2, with pombe rgs1 as an outgroup The metazoan clades are: AN4 Drosophila Axin, vertebrate RGS9 and RGS11 clades AN69 3 uncharacterized proteins from dog, Ciona, and mosquito AN74 Drosophila loco, vertebrate RGS10, -12, and -14 AN146 Worm eat-16 and egl-10, vertebrate RGS6 and -7 AN222 vertebrate RGS1, -19, and -20, plus an uncharacterized worm/fly outgroup. AN316 Worm outgroup plus 3 deuterostome clades (human to urchin) The deuterostome clades in AN316 are: AN318 Axin1 and Axin2 clades AN375 RGS22 AN398 urchin and Ciona outgroups, plus many vertebrate RGS clades We are primarily interested in the vertebrate Axin1 and Axin2 clades, so we will focus our attention there, using outside information primarily for perspective. MF -GO:0019901 "protein kinase binding" and GO:0008013 "beta-catenin binding" are found in both the Axin1 and Axin 2 clades and should be propagated to AN318 as the common ancestor. GO:0070016 armadillo repeat domain binding is found only on rat Axin1, but the paper (PMID 9482734) says that axin binds the armadillo repeats of beta-catenin. Since we're propagating GO:0008013 "beta-catenin binding" to both clades, also propagate 70016 to both clades. None of these annotations are found outside the Axin1/2 clade. -There are many annotations throughout the entire family, including in the yeast and Arabidopsis outgroups, to GO:0005096 "GTPase activator activity." Propagate to AN0. CC -There are no annotations to the Axin2 clade. However, Axin2 is cytoplasmic and seems to function in most of the same places as Axin1 (see PMID 9554852), so include the Axin2 clade in all Axin1 propagations. These are: GO:0016023 cytoplasmic membrane-bounded vesicle GO:0005881 cytoplasmic microtubule GO:0014069 postsynaptic density GO:0034747 Axin-APC-beta-catenin-GSK3B complex GO:0005938 cell cortex -"Cell cortex" seems a more apt description of the location of axin than GO:0005886 "plasma membrane," but 5886 could include accessory proteins AND there are widespread annotations to 5886 in the family, including on the Arabidopsis outgroup. Propagate 5886 to AN0. Also propagate "cytoplasm" to AN0, but don't propagate "nucleus" at this time because it seems that there are definitely some proteins that do not go to the nucleus. BP Start with pathway terms such as Wnt pathway, JNK cascade, and regulation of JUN kinase activity": -There are multiple annotations to GO:0030178 "negative regulation of Wnt receptor signaling pathway" from Danio to rat covering both clades. There are also 2 annotations to GO:0090090 "negative regulation of canonical Wnt receptor signaling pathway" in the Axin1 clade. Propagate 90090 to AN318. -There are multiple annotations to kinase and phosphorylation terms in the Axin1 clade, but none in the Axin2 clade. Propagate GO:0007257 "activation of JUN kinase activity" to the Axin1 clade. -There is one annotation to GO:0035412 "regulation of catenin protein nuclear translocation" in the Axin1 clade, but we propagated 34747 to both clades above, so propagate 35412 to AN318. Pathway/development cross-products: -GO:0090244 "Wnt receptor signaling pathway involved in somitogenesis" is used for Danio axin1. Mouse Axin2 has an annotation to GO:0001756 "somitogenesis" and multiple annotations, both experimental and inferred through PAINT, to children of "Wnt receptor signaling pathway." Propagate 90244 to all the axins. -GO:0021881 "Wnt receptor signaling pathway involved in forebrain neuron fate commitment" used for Danio axin1, and no Axin2's are annotated to any children of GO:0007399 "nervous system development." Propagate 21881 to the Axin1 clade. Similar argument for GO:0060823 "canonical Wnt receptor signaling pathway involved in neural plate anterior/posterior pattern formation." Transcription: -GO:0090041 "negative regulation of gene-specific transcription elongation from RNA polymerase II promoter" is used in the Axin1 clade, but no transcriptional terms are used in the Axin2 clade. However, transcriptional regulation is an endpoint of the Wnt pathway, so it is reasonable to infer that a protein that is involved in the Wnt pathway is involved in transcriptional regulation. Propagate 90041 to the Axin1 clade and GO:0045449 "regulation of transcription" to AN318 to cover both clades. Cellular differentiation: -GO:0045599 "negative regulation of fat cell differentiation" and GO:0055001 "muscle cell development" are found only in the Axin1 clade; propagate to the rest of the clade. Similarly, propagate GO:0045668 "negative regulation of osteoblast differentiation" to the Axin2 clade. Propagate the parental term GO:0030154 "cell differentiation" to AN318. Organs: -Propagate GO:0021797 "forebrain anterior/posterior pattern formation"from Danio axin1 to the Axin1 clade. No neuro development terms are used in the Axin2 clade. -Propagate GO:0048048 "embryonic eye morphogenesis" from Danio to the Axin1 clade. -Propagate GO:0060272 "embryonic skeletal joint morphogenesis" and GO:0035121 "tail morphogenesis" from mouse to Axin1 clade. -Propagate GO:0001957 "intramembranous ossification" to Axin2 clade as for 45668 above. Embryonic tissues: -Propagate GO:0048320 "axial mesoderm formation" to Axin1 clade. -Propagate GO:0030910 "olfactory placode formation" and GO:0001743 "optic placode formation" from Danio to Axin1 clade. Pattern specification: -Propagate GO:0007368 "determination of left/right symmetry" to the Axin 1 clade. -GO:0009953 "dorsal/ventral pattern formation" is used directly for Danio axin1 & -2. The child term "GO:0009950 "dorsal/ventral axis specification" is used for mouse Axin 1. However, PMID 10704853 seems to say that Danio axin2 is involved in 9950, not just 9953. Propagate 9950 to AN318 to cover both clades. Other cellular processes: -Propagate GO:0071407 "cellular response to organic cyclic substance" to AN318. PMID 19464575 shows adherens junctions degrading in response to PCB 153, and Axin2 levels change. -Propagate GO:0031122 "cytoplasmic microtubule organization" to the Axin1 clade. Do not propagate to the Axin2 clade (PMID 19390532). -GO:0008219 "cell death" is found on rat Axin2 and is a consequence of down-regulation of Wnt signaling (PMID 15572025). Ergo propagate 8219 to all the axins. Cannot verify annotations from MGI reference #48782, published 1954. Questions arising during PAINT curation of the Axin1/2 family. Note: this is a large family of regulators of G-protein signaling, but this initial PAINT curation if focused on just the Axin 1&2 clades. Contents * 1 Questions for MOD curators o 1.1 Phylogeny + 1.1.1 Fly o 1.2 MF + 1.2.1 Mouse + 1.2.2 Rat o 1.3 CC + 1.3.1 All organisms + 1.3.2 Mouse o 1.4 BP + 1.4.1 All organisms + 1.4.2 Mouse + 1.4.3 Zebrafish * 2 Questions for ontology curators o 2.1 BP Questions for MOD curators Phylogeny Fly * Please confirm that fly Axn is placed properly in AN4 clade instead of AN316 clade. Note the annotation to GO:0030178, the long branch lengths to Axn and AN63, and the existence of the current paralog FBgn0030962. MF Mouse * Axin 1 & Axin2: Can you make the "protein binding" annotations more specific? For axin1, there are also several annotations to children of "protein binding" that could possibly be more specific. * Axin1: Does PMID 10318824 actually show GO:0016566 "specific transcriptional repressor activity" as a MF of Axin, or does it just show that Axin participates in the BP GO:0016481 "negative regulation of transcription"? Rat * Axin1: Can you make the "protein binding" annotations more specific? CC All organisms * There are no CC annotations for any of the Axin2's. Human has GO:0005813 centrosome IDA from PMID: 20300119 [VK] Mouse * GO:0048222 "glycoprotein network" is a child of "cell wall." Is this annotation appropriate for mouse? BP All organisms * Is there any evidence that Axin2 regulates JUN kinase activity or the JNK cascade? That it regulates any kinase activity at all? * Is there any evidence that Axin2 is involved in transcriptional regulation? Mouse * Can you make the annotations to GO:0030163 "protein catabolic process" and/or GO:0051248 "negative regulation of protein metabolic process" more specific? * Is Axin1 involved in GO:0071514 "genetic imprinting," or is it just that it gets imprinted (PMID 12601169)? * Please verify annotations from MGI refs #48782 and #48780, which are 50+ years old. Zebrafish * For the "eye development" and "embryonic eye morphogenesis" annotations, please specify the "camera-type" child terms. Questions for ontology curators BP * Should GO:0043507 "positive regulation of JUN kinase activity" be part_of GO:0046330 "positive regulation of JNK cascade"? Submitted 2010 Nov 9, MSL Revised 2010 Dec 22, MSL # REFERENCE Annotation inferences using phylogenetic trees The goal of the GO Reference Genome Project, described in PMID 19578431, is to provide accurate, complete and consistent GO annotations for all genes in twelve model organism genomes. To this end, GO curators are annotating evolutionary trees from the PANTHER database with GO terms describing molecular function, biological process and cellular component. GO terms based on experimental data from the scientific literature are used to annotate ancestral genes in the phylogenetic tree by sequence similarity (ISS), and unannotated descendants of these ancestral genes are inferred to have inherited these same GO annotations by descent. The annotations are done using a tool called PAINT (Phylogenetic Annotation and INference Tool).