KRIT1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0001937 negative regulation of endothelial cell proliferation	IMP PMID:20616044 Cerebral cavernous malformation protein CCM1 inhibits sprout...	KEEP AS NON CORE	Summary: CCM1 depletion increases human endothelial proliferation. Reason: Primary human endothelial cells depleted of CCM1 show increased proliferation, migration, apoptosis, lumen formation and sprouting (PMID:20616044). These quiescence-maintaining effects are real and consistent with the IBA/IMP rows for negative regulation of angiogenesis, but they are downstream outputs of the junctional Rap1-effector and adaptor activities (via DLL4-NOTCH and MEKK3 restraint), so they are kept as non-core. Supporting Evidence: PMID:20616044 CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells.
GO:0003158 endothelium development	NAS PMID:17657516 CCM3 interacts with CCM2 indicating common pathogenesis for ...	KEEP AS NON CORE	Summary: Endothelium development is a downstream developmental context of KRIT1 function. Reason: This NAS row comes from a paper on CCM3-CCM2 binding that discusses the CCM genes in general. Independent evidence shows KRIT1-Rap1 binding is required for cardiovascular development and that KRIT1 maintains endothelial quiescence and junctions. Endothelium development is therefore a compatible but downstream organismal process for a junctional adaptor and is kept as non-core. Supporting Evidence: PMID:21633110 Direct binding of KRIT1 to Rap1 stabilized endothelial cell-cell junctions in vitro and was required for cardiovascular development in vivo. PMID:20616044 CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells.
GO:0005515 protein binding	IPI PMID:16037064 CCM1 and CCM2 protein interactions in cell signaling: implic...	REMOVE	Summary: Generic protein binding to CCM2; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-CCM2 interaction is well established (CCM2 PTB domain binding the KRIT1 NPXY/F motifs), and its functional content is captured by the adaptor-activity refinement of the PMID:23007647 rows. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:17657516 CCM3 interacts with CCM2 indicating common pathogenesis for ...	REMOVE	Summary: Generic protein binding to CCM2; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-CCM2 interaction is well established (CCM2 PTB domain binding the KRIT1 NPXY/F motifs), and its functional content is captured by the adaptor-activity refinement of the PMID:23007647 rows. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:17916086 Krit 1 interactions with microtubules and membranes are regu...	REMOVE	Summary: Generic protein binding to ITGB1BP1/ICAP1; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-ICAP1 interaction is real and functionally important (it underlies KRIT1 antagonism of ICAP1-mediated integrin suppression, captured here by the integrin activation row), but there is no GO molecular-function term for ICAP1 binding. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:17916086 Krit 1 interactions with microtubules and membranes are regu...	MODIFY	Summary: KRIT1 binds GTP-loaded RAP1A; the informative activity is small GTPase binding. Reason: PMID:17916086 shows by biochemical assays that KRIT1 binds RAP1A, preferentially the GTP-bound form, through the FERM domain. Later structural and mutagenesis work (PMID:21633110, PMID:22577140) confirms KRIT1 as a Rap1-specific effector. The generic protein-binding row is replaced by small GTPase binding, which the review also proposes for the GTPase regulator activity rows. Proposed replacements: small GTPase binding Supporting Evidence: PMID:17916086 Krit1 interacts with Rap1A, preferentially its GTP-bound form PMID:22577140 We report the 1.95 Å co-crystal structure of KRIT1 FERM domain in complex with Rap1.
GO:0005515 protein binding	IPI PMID:20332120 CCM1 regulates vascular-lumen organization by inducing endot...	MODIFY	Summary: KRIT1 associates with VE-cadherin at endothelial adherens junctions. Reason: PMID:20332120 reports that CCM1 interacts with VE-cadherin and directs adherens junction organization; KRIT1 and CDH5 reciprocally control each other's junctional localization. The interaction partner defines a more informative molecular function than generic protein binding, so the row is refined to cadherin binding. The abstract does not say whether binding is direct, so this is a non-core refinement. Proposed replacements: cadherin binding Supporting Evidence: PMID:20332120 The protein interacts with VEC and directs AJ organization
GO:0005515 protein binding	IPI PMID:23007647 Structural basis of the junctional anchorage of the cerebral...	MODIFY	Summary: KRIT1 binding to CCM2 is part of its adaptor role linking CCM2 to HEG1 at endothelial junctions. Reason: PMID:23007647 measures direct binding of the KRIT1 FERM domain to the HEG1 C terminus (Kd 1.2 uM), solves the structure, and shows that a HEG1-binding-defective KRIT1 mutant fails to reach endothelial junctions. UniProt records from this paper that KRIT1 greatly facilitates CCM2 binding to HEG1. Simultaneous binding of the transmembrane HEG1 tail and the CCM2 PTB domain to anchor the CCM complex is a molecular adaptor activity, so this generic protein-binding row for CCM2 is refined to protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:23007647 CCM1/KRIT1 links this complex to endothelial cell (EC) junctions file:human/KRIT1/KRIT1-uniprot.txt Interacts with HEG1 and CCM2; greatly facilitates CCM2-binding to HEG1.
GO:0005515 protein binding	IPI PMID:23007647 Structural basis of the junctional anchorage of the cerebral...	MODIFY	Summary: KRIT1 binding to HEG1 is part of its adaptor role linking CCM2 to HEG1 at endothelial junctions. Reason: PMID:23007647 measures direct binding of the KRIT1 FERM domain to the HEG1 C terminus (Kd 1.2 uM), solves the structure, and shows that a HEG1-binding-defective KRIT1 mutant fails to reach endothelial junctions. UniProt records from this paper that KRIT1 greatly facilitates CCM2 binding to HEG1. Simultaneous binding of the transmembrane HEG1 tail and the CCM2 PTB domain to anchor the CCM complex is a molecular adaptor activity, so this generic protein-binding row for HEG1 is refined to protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:23007647 CCM1/KRIT1 links this complex to endothelial cell (EC) junctions file:human/KRIT1/KRIT1-uniprot.txt Interacts with HEG1 and CCM2; greatly facilitates CCM2-binding to HEG1.
GO:0005515 protein binding	IPI PMID:25525273 Structural basis for the disruption of the cerebral cavernou...	REMOVE	Summary: Generic protein binding to CCM2; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-CCM2 interaction is well established (CCM2 PTB domain binding the KRIT1 NPXY/F motifs), and its functional content is captured by the adaptor-activity refinement of the PMID:23007647 rows. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:25814554 Phospho-tyrosine dependent protein-protein interaction netwo...	REMOVE	Summary: Generic protein binding to ITGB1BP1/ICAP1; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-ICAP1 interaction is real and functionally important (it underlies KRIT1 antagonism of ICAP1-mediated integrin suppression, captured here by the integrin activation row), but there is no GO molecular-function term for ICAP1 binding. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:25814554 Phospho-tyrosine dependent protein-protein interaction netwo...	REMOVE	Summary: Generic protein binding to CCM2; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-CCM2 interaction is well established (CCM2 PTB domain binding the KRIT1 NPXY/F motifs), and its functional content is captured by the adaptor-activity refinement of the PMID:23007647 rows. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	REMOVE	Summary: Generic protein binding to ITGB1BP1/ICAP1; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-ICAP1 interaction is real and functionally important (it underlies KRIT1 antagonism of ICAP1-mediated integrin suppression, captured here by the integrin activation row), but there is no GO molecular-function term for ICAP1 binding. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	REMOVE	Summary: Generic protein binding to CCM2; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-CCM2 interaction is well established (CCM2 PTB domain binding the KRIT1 NPXY/F motifs), and its functional content is captured by the adaptor-activity refinement of the PMID:23007647 rows. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:26780829 Heart of glass anchors Rasip1 at endothelial cell-cell junct...	REMOVE	Summary: Generic protein binding to HEG1; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-HEG1 interaction is well established, and its functional content is captured by the adaptor-activity refinement of the PMID:23007647 rows. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:27027284 Cerebral cavernous malformations arise from endothelial gain...	REMOVE	Summary: Generic protein binding to CCM2 isoform 1; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-CCM2 interaction is well established (CCM2 PTB domain binding the KRIT1 NPXY/F motifs), and its functional content is captured by the adaptor-activity refinement of the PMID:23007647 rows. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Generic protein binding to UBE2K; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. This is a high-throughput binary interactome hit with no follow-up linking it to a KRIT1 function. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Generic protein binding to ITGB1BP1/ICAP1; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-ICAP1 interaction is real and functionally important (it underlies KRIT1 antagonism of ICAP1-mediated integrin suppression, captured here by the integrin activation row), but there is no GO molecular-function term for ICAP1 binding. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Generic protein binding to CCM2; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-CCM2 interaction is well established (CCM2 PTB domain binding the KRIT1 NPXY/F motifs), and its functional content is captured by the adaptor-activity refinement of the PMID:23007647 rows. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Generic protein binding to HEG1; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-HEG1 interaction is well established, and its functional content is captured by the adaptor-activity refinement of the PMID:23007647 rows. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	REMOVE	Summary: Generic protein binding to CCM2; uninformative as a molecular function. Reason: Bare protein binding (GO:0005515) carries no functional information. The KRIT1-CCM2 interaction is well established (CCM2 PTB domain binding the KRIT1 NPXY/F motifs), and its functional content is captured by the adaptor-activity refinement of the PMID:23007647 rows. Removal follows the repository protein-binding policy and does not mean the reported interaction is false.
GO:0005546 phosphatidylinositol-4,5-bisphosphate binding	IDA PMID:17916086 Krit 1 interactions with microtubules and membranes are regu...	ACCEPT	Summary: KRIT1 binds PI(4,5)P2-containing membranes, enhanced by Rap1. Reason: Sedimentation assays show direct binding of KRIT1 to PI(4,5)P2-containing liposomes, and UniProt notes that the FERM domain is necessary for this binding. The activity is part of the mechanism by which Rap1 captures KRIT1 at the plasma membrane. Supporting Evidence: PMID:17916086 Krit1 binds to phosphatidylinositol 4,5-P(2)-containing liposomes and that Rap1 enhances this binding
GO:0005576 extracellular region	HDA PMID:22664934 Comparison of tear protein levels in breast cancer patients ...	MARK AS OVER ANNOTATED	Summary: Detection in a tear-fluid proteomics survey; not a physiological location of KRIT1. Reason: The row comes from a high-throughput tear-fluid proteomics comparison; KRIT1 is not mentioned in the cached full text, so it is presumably in a supplementary list. KRIT1 has no signal peptide or transmembrane segment and every targeted study places it on microtubules, at the plasma membrane and at cell-cell junctions. Detection in tears most plausibly reflects shed epithelial cells or debris. The curated detection is not disputed, but extracellular region overstates KRIT1 biology. Supporting Evidence: file:human/KRIT1/KRIT1-uniprot.txt Association with RAP1 relocalizes KRIT1 from microtubules to cell junction membranes.
GO:0005737 cytoplasm	IEA GO_REF:0000107	MODIFY	Summary: Cytoplasmic pool of KRIT1 is microtubule-associated. Reason: Correct but general. The documented cytoplasmic pool of KRIT1 is bound to microtubules through its N and C termini, in vitro and in cells, before Rap1 releases it. The more specific supported location is microtubule cytoskeleton. Proposed replacements: microtubule cytoskeleton Supporting Evidence: PMID:17916086 Krit1 binds in vitro to microtubules through its N- and C-termini PMID:17916086 YFP-Krit1 localizes on cyan fluorescent protein-labelled microtubules
GO:0005856 cytoskeleton	IEA GO_REF:0000044	MODIFY	Summary: KRIT1 associates with microtubules. Reason: Correct but general (UniProt SubCell 'cytoskeleton' mapping). KRIT1 associates with microtubules specifically, so microtubule cytoskeleton is the supported refinement. This is a sequestration site from which Rap1 and ICAP1 release KRIT1, not a motor function. Proposed replacements: microtubule cytoskeleton Supporting Evidence: PMID:17916086 Krit1 binds in vitro to microtubules through its N- and C-termini PMID:17916086 YFP-Krit1 localizes on cyan fluorescent protein-labelled microtubules
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: KRIT1 is recruited to the plasma membrane by Rap1 and PI(4,5)P2. Reason: KRIT1 is a peripheral membrane protein: its FERM domain binds PI(4,5)P2-containing liposomes, Rap1 enhances this binding (PMID:17916086), and Rap1 relocalizes KRIT1 from microtubules to junctional membranes (PMID:21633110). The PAINT node PTN004412369 spans the KRIT1/FRMD8 family (seeds include human FRMD8 and worm kri-1), and plasma membrane localization is consistent across the family. The IBA, IDA and IEA rows reinforce one another. Supporting Evidence: PMID:17916086 Krit1 binds to phosphatidylinositol 4,5-P(2)-containing liposomes and that Rap1 enhances this binding PMID:21633110 Rap1 binding released KRIT1 from microtubules, enabling it to locate to cell--cell junctions, where it suppressed Rho kinase signaling and stabilized the junctions
GO:0005886 plasma membrane	IDA PMID:17916086 Krit 1 interactions with microtubules and membranes are regu...	ACCEPT	Summary: KRIT1 is recruited to the plasma membrane by Rap1 and PI(4,5)P2. Reason: KRIT1 is a peripheral membrane protein: its FERM domain binds PI(4,5)P2-containing liposomes, Rap1 enhances this binding (PMID:17916086), and Rap1 relocalizes KRIT1 from microtubules to junctional membranes (PMID:21633110). The PAINT node PTN004412369 spans the KRIT1/FRMD8 family (seeds include human FRMD8 and worm kri-1), and plasma membrane localization is consistent across the family. The IBA, IDA and IEA rows reinforce one another. Supporting Evidence: PMID:17916086 Krit1 binds to phosphatidylinositol 4,5-P(2)-containing liposomes and that Rap1 enhances this binding
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: KRIT1 is recruited to the plasma membrane by Rap1 and PI(4,5)P2. Reason: KRIT1 is a peripheral membrane protein: its FERM domain binds PI(4,5)P2-containing liposomes, Rap1 enhances this binding (PMID:17916086), and Rap1 relocalizes KRIT1 from microtubules to junctional membranes (PMID:21633110). The PAINT node PTN004412369 spans the KRIT1/FRMD8 family (seeds include human FRMD8 and worm kri-1), and plasma membrane localization is consistent across the family. The IBA, IDA and IEA rows reinforce one another. Supporting Evidence: PMID:17916086 Krit1 binds to phosphatidylinositol 4,5-P(2)-containing liposomes and that Rap1 enhances this binding file:human/KRIT1/KRIT1-uniprot.txt Association with RAP1 relocalizes KRIT1 from microtubules to cell junction membranes.
GO:0005911 cell-cell junction	IDA PMID:20332120 CCM1 regulates vascular-lumen organization by inducing endot...	ACCEPT	Summary: KRIT1 localizes to endothelial cell-cell junctions. Reason: Junctional localization is the site of KRIT1 action. HEG1 binding anchors KRIT1 at endothelial cell-cell junctions (a HEG1-binding-defective mutant fails to target there; PMID:23007647), and Rap1 binding releases KRIT1 from microtubules so it can reach junctions (PMID:21633110). Both IDA rows are accepted. Supporting Evidence: PMID:20332120 The protein interacts with VEC and directs AJ organization and AJ association with the polarity complex PMID:21633110 Rap1 binding released KRIT1 from microtubules, enabling it to locate to cell--cell junctions, where it suppressed Rho kinase signaling and stabilized the junctions
GO:0005911 cell-cell junction	IDA PMID:23007647 Structural basis of the junctional anchorage of the cerebral...	ACCEPT	Summary: HEG1 binding anchors KRIT1 at endothelial cell-cell junctions. Reason: Junctional localization is the site of KRIT1 action. HEG1 binding anchors KRIT1 at endothelial cell-cell junctions (a HEG1-binding-defective mutant fails to target there; PMID:23007647), and Rap1 binding releases KRIT1 from microtubules so it can reach junctions (PMID:21633110). Both IDA rows are accepted. Supporting Evidence: PMID:23007647 KRIT1(L717,721A) failed to target to EC junctions
GO:0007264 small GTPase-mediated signal transduction	TAS PMID:9285558 Association of Krev-1/rap1a with Krit1, a novel ankyrin repe...	ACCEPT	Summary: KRIT1 is a Rap1-specific effector in small GTPase signaling. Reason: The original two-hybrid paper (abstract only) proposed a Krev-1/Rap1A link with a truncated clone; a later study failed to see the interaction with full-length KRIT1 (PMID:11741838), but GTP-dependent binding to the Rap1 effector loop was subsequently established biochemically, structurally and by mutagenesis. KRIT1 executes a step of Rap1 signaling as its effector, so the process term is accepted as core. Supporting Evidence: PMID:21633110 native KRIT1 protein binds the effector loop of Rap1A but not H-Ras in a GTP-dependent manner PMID:21633110 Rap1 binding released KRIT1 from microtubules, enabling it to locate to cell--cell junctions, where it suppressed Rho kinase signaling and stabilized the junctions
GO:0008017 microtubule binding	IBA GO_REF:0000033	ACCEPT	Summary: KRIT1 binds microtubules through its N and C termini. Reason: PAINT placed microtubule binding at PTN002665063 (bilaterian KRIT1 clade) with human KRIT1 itself as the experimental seed; the target appearing among the sources is expected. The IBA and IDA rows reinforce each other. Microtubule binding regulates KRIT1 availability for junctional recruitment. Supporting Evidence: PMID:17916086 Krit1 binds in vitro to microtubules through its N- and C-termini
GO:0008017 microtubule binding	IDA PMID:17916086 Krit 1 interactions with microtubules and membranes are regu...	ACCEPT	Summary: KRIT1 binds microtubules through its N and C termini. Reason: Microtubule co-sedimentation of purified KRIT1, decoration of microtubules by YFP-KRIT1 in cells, and release by activated Rap1 or ICAP1 directly support microtubule binding. Supporting Evidence: PMID:17916086 Krit1 binds in vitro to microtubules through its N- and C-termini PMID:17916086 YFP-Krit1 localizes on cyan fluorescent protein-labelled microtubules
GO:0009948 anterior/posterior axis specification	IBA GO_REF:0000033	REMOVE	Summary: Anterior/posterior axis specification is not a KRIT1 process; the propagation rests on a knockdown body-axis phenotype. Reason: The only seed for this PTN002665063 assertion is a ZFIN acts_upstream_of_or_within IGI annotation to zebrafish krit1 from PMID:26540726, where combined knockdown of ccm2l and ccm2 caused cardiac and circulation defects with secondary 'body axis abnormalities' that MEKK3 silencing rescued. That is a downstream organismal phenotype of vascular/cardiac CCM-MEKK3 dysregulation, not patterning of the A/P axis, and the upstream relationship is lost when the IBA is emitted as involved_in. No mammalian KRIT1 study implicates axis specification. The term is removed on biological grounds. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: CONTEXT OR TISSUE MISMATCH SOURCE EVIDENCE WEAK Sources checked: PANTHER:PTN002665063 · bilaterian KRIT1 clade node SOURCE WEAK OR INFERRED Node placement is not in question (human, mouse and zebrafish KRIT1 all descend from it); the single seed for this term is weak. ZFIN:ZDB-GENE-030131-555 · zebrafish krit1 SOURCE WEAK OR INFERRED acts_upstream_of_or_within IGI from PMID:26540726: secondary body-axis abnormalities in ccm2l/ccm2 knockdown embryos, an organismal phenotype rather than A/P axis specification. Supporting Evidence: PMID:26540726 A knockdown of ccm2l and ccm2 in zebrafish leads to a more severe "big heart" and circulation defects compared with loss of function of ccm2 alone, and also leads to substantial body axis abnormalities.
GO:0010596 negative regulation of endothelial cell migration	IMP PMID:20616044 Cerebral cavernous malformation protein CCM1 inhibits sprout...	KEEP AS NON CORE	Summary: CCM1 depletion increases human endothelial migration. Reason: Primary human endothelial cells depleted of CCM1 show increased proliferation, migration, apoptosis, lumen formation and sprouting (PMID:20616044). These quiescence-maintaining effects are real and consistent with the IBA/IMP rows for negative regulation of angiogenesis, but they are downstream outputs of the junctional Rap1-effector and adaptor activities (via DLL4-NOTCH and MEKK3 restraint), so they are kept as non-core. Supporting Evidence: PMID:20616044 CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells.
GO:0016525 negative regulation of angiogenesis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: KRIT1 restrains angiogenic sprouting. Reason: KRIT1 restrains angiogenic sprouting: CCM1 loss in primary human endothelial cells increases sprouting, and PAINT curators placed this term at PTN002665064 (vertebrate KRIT1 clade) with human and mouse experimental seeds. KRIT1 is in the same PANTHER subfamily (PTHR13283:SF11) as the mouse seed. The term is correct, but it describes a tissue-level output of junction stabilization and NOTCH/MEKK3 signaling control rather than the molecular activity of KRIT1, so it is retained as non-core; the IBA, IEA and IMP rows are judged together. Supporting Evidence: PMID:20616044 CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells.
GO:0016525 negative regulation of angiogenesis	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: KRIT1 restrains angiogenic sprouting. Reason: KRIT1 restrains angiogenic sprouting: CCM1 loss in primary human endothelial cells increases sprouting, and PAINT curators placed this term at PTN002665064 (vertebrate KRIT1 clade) with human and mouse experimental seeds. KRIT1 is in the same PANTHER subfamily (PTHR13283:SF11) as the mouse seed. The term is correct, but it describes a tissue-level output of junction stabilization and NOTCH/MEKK3 signaling control rather than the molecular activity of KRIT1, so it is retained as non-core; the IBA, IEA and IMP rows are judged together. Supporting Evidence: PMID:20616044 CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells.
GO:0016525 negative regulation of angiogenesis	IMP PMID:20616044 Cerebral cavernous malformation protein CCM1 inhibits sprout...	KEEP AS NON CORE	Summary: KRIT1 restrains angiogenic sprouting. Reason: KRIT1 restrains angiogenic sprouting: CCM1 loss in primary human endothelial cells increases sprouting, and PAINT curators placed this term at PTN002665064 (vertebrate KRIT1 clade) with human and mouse experimental seeds. KRIT1 is in the same PANTHER subfamily (PTHR13283:SF11) as the mouse seed. The term is correct, but it describes a tissue-level output of junction stabilization and NOTCH/MEKK3 signaling control rather than the molecular activity of KRIT1, so it is retained as non-core; the IBA, IEA and IMP rows are judged together. Supporting Evidence: PMID:20616044 CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells.
GO:0030695 GTPase regulator activity	IEA GO_REF:0000117	MODIFY	Summary: KRIT1 is a Rap1 effector, not a regulator of GTPase activity. Reason: GTPase regulator activity implies modulating the GTPase cycle (GEF, GAP or GDI-like). No study shows KRIT1 altering Rap1 nucleotide exchange or hydrolysis; instead KRIT1 binds the GTP-loaded Rap1 effector loop and is relocalized by it, the defining behavior of an effector. The ARBA-derived term is replaced by small GTPase binding. Proposed replacements: small GTPase binding Supporting Evidence: PMID:21633110 native KRIT1 protein binds the effector loop of Rap1A but not H-Ras in a GTP-dependent manner
GO:0030695 GTPase regulator activity	TAS PMID:9285558 Association of Krev-1/rap1a with Krit1, a novel ankyrin repe...	MODIFY	Summary: KRIT1 is a Rap1 effector, not a regulator of GTPase activity. Reason: The 1997 two-hybrid paper speculated that KRIT1 'might specifically regulate Krev-1 activities' without any GTPase assay. Later direct binding and mutagenesis establish KRIT1 as a GTP-dependent Rap1 effector rather than a GEF or GAP, so the term is replaced by small GTPase binding. Proposed replacements: small GTPase binding Supporting Evidence: PMID:21633110 native KRIT1 protein binds the effector loop of Rap1A but not H-Ras in a GTP-dependent manner PMID:9285558 Krit1 interacted strongly with Krev-1 but only weakly with Ras
GO:0032991 protein-containing complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: KRIT1 is a component of the CCM adaptor complex with CCM2 and PDCD10. Reason: KRIT1 forms a defined adaptor assembly with CCM2 (and through CCM2 with PDCD10/CCM3 and MEKK3), and a ternary KRIT1-RAP1A-ICAP1 complex. GO has no specific complex term for the CCM complex (OLS search returned none), so the generic term is as precise as the ontology allows. It is kept as non-core. Supporting Evidence: PMID:27027284 CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. PMID:16037064 CCM1 associates with CCM2 and MEKK3 in a ternary complex
GO:0033622 integrin activation	IDA PMID:23317506 Mechanism for KRIT1 release of ICAP1-mediated suppression of...	MODIFY	Summary: KRIT1 releases ICAP1-mediated suppression of beta1 integrin activation. Reason: KRIT1 does not itself activate integrins; it binds ICAP1 through a bidentate surface, competes with the beta1 integrin tail for ICAP1, and so antagonizes ICAP1 inhibition of inside-out activation. That is a positive regulatory role, better captured by positive regulation of integrin activation. Proposed replacements: positive regulation of integrin activation Supporting Evidence: PMID:23317506 KRIT1 functions as a switch for β1 integrin activation by antagonizing ICAP1 PMID:23317506 KRIT1 directly competes with integrin β1 to bind ICAP1
GO:0045454 cell redox homeostasis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: KRIT1 indirectly limits intracellular ROS via FOXO1/SOD2. Reason: KRIT1-null MEFs have elevated ROS with reduced FOXO1 and SOD2, rescued by KRIT1 re-expression, and HUVEC knockdown lowers FOXO1 and SOD2 mRNA (PMID:20668652, full text). PAINT placed this term at PTN002665063 with human and mouse seeds, and the C. elegans ortholog kri-1 acts through DAF-16/FOXO. KRIT1 has no redox chemistry; its effect is regulatory (Akt/FOXO1-dependent antioxidant gene expression). The term is kept as a non-core, indirect role; IBA, IEA and IMP rows are judged together. Supporting Evidence: PMID:20668652 KRIT1 loss/down-regulation is associated with a significant increase in intracellular ROS levels
GO:0045454 cell redox homeostasis	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: KRIT1 indirectly limits intracellular ROS via FOXO1/SOD2. Reason: KRIT1-null MEFs have elevated ROS with reduced FOXO1 and SOD2, rescued by KRIT1 re-expression, and HUVEC knockdown lowers FOXO1 and SOD2 mRNA (PMID:20668652, full text). PAINT placed this term at PTN002665063 with human and mouse seeds, and the C. elegans ortholog kri-1 acts through DAF-16/FOXO. KRIT1 has no redox chemistry; its effect is regulatory (Akt/FOXO1-dependent antioxidant gene expression). The term is kept as a non-core, indirect role; IBA, IEA and IMP rows are judged together. Supporting Evidence: PMID:20668652 KRIT1 loss/down-regulation is associated with a significant increase in intracellular ROS levels
GO:0045454 cell redox homeostasis	IMP PMID:20668652 KRIT1 regulates the homeostasis of intracellular reactive ox...	KEEP AS NON CORE	Summary: KRIT1 indirectly limits intracellular ROS via FOXO1/SOD2. Reason: KRIT1-null MEFs have elevated ROS with reduced FOXO1 and SOD2, rescued by KRIT1 re-expression, and HUVEC knockdown lowers FOXO1 and SOD2 mRNA (PMID:20668652, full text). PAINT placed this term at PTN002665063 with human and mouse seeds, and the C. elegans ortholog kri-1 acts through DAF-16/FOXO. KRIT1 has no redox chemistry; its effect is regulatory (Akt/FOXO1-dependent antioxidant gene expression). The term is kept as a non-core, indirect role; IBA, IEA and IMP rows are judged together. Supporting Evidence: PMID:20668652 KRIT1 loss/down-regulation is associated with a significant increase in intracellular ROS levels
GO:0045765 regulation of angiogenesis	NAS PMID:17657516 CCM3 interacts with CCM2 indicating common pathogenesis for ...	MODIFY	Summary: Regulation of angiogenesis is correct but less specific than the supported negative regulation. Reason: KRIT1 restrains sprouting angiogenesis (PMID:20616044), and the gene already carries GO:0016525 negative regulation of angiogenesis by IBA and IMP. The general NAS term is refined to that descendant. Proposed replacements: negative regulation of angiogenesis Supporting Evidence: PMID:20616044 CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells.
GO:0070161 anchoring junction	IEA GO_REF:0000044	MODIFY	Summary: KRIT1 acts at VE-cadherin-based adherens junctions. Reason: Correct but general (UniProt SubCell 'cell junction' mapping). CCM1 interacts with VE-cadherin and directs adherens junction organization, and KRIT1 and CDH5 reciprocally control their junctional localization. Adherens junction, a descendant of anchoring junction, is the supported refinement. Proposed replacements: adherens junction Supporting Evidence: PMID:20332120 The protein interacts with VEC and directs AJ organization and AJ association with the polarity complex
GO:2000114 regulation of establishment of cell polarity	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: KRIT1 is required for endothelial apicobasal polarity through junction organization. Reason: CCM1 interacts with VE-cadherin and directs adherens junction association with the Par3/PKCzeta polarity complex; in its absence apicobasal polarity and lumen organization are lost (PMID:20332120). PAINT placed the term at PTN002665063 with human and mouse seeds. This is a supported regulatory role that follows from KRIT1 junctional organization, so it is kept as non-core rather than as a core molecular function. IBA, IEA and IMP rows are judged together. Supporting Evidence: PMID:20332120 In the absence of any of these proteins, AJs are dismantled, cell polarity is lost
GO:2000114 regulation of establishment of cell polarity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: KRIT1 is required for endothelial apicobasal polarity through junction organization. Reason: CCM1 interacts with VE-cadherin and directs adherens junction association with the Par3/PKCzeta polarity complex; in its absence apicobasal polarity and lumen organization are lost (PMID:20332120). PAINT placed the term at PTN002665063 with human and mouse seeds. This is a supported regulatory role that follows from KRIT1 junctional organization, so it is kept as non-core rather than as a core molecular function. IBA, IEA and IMP rows are judged together. Supporting Evidence: PMID:20332120 In the absence of any of these proteins, AJs are dismantled, cell polarity is lost
GO:2000114 regulation of establishment of cell polarity	IMP PMID:20332120 CCM1 regulates vascular-lumen organization by inducing endot...	KEEP AS NON CORE	Summary: KRIT1 is required for endothelial apicobasal polarity through junction organization. Reason: CCM1 interacts with VE-cadherin and directs adherens junction association with the Par3/PKCzeta polarity complex; in its absence apicobasal polarity and lumen organization are lost (PMID:20332120). PAINT placed the term at PTN002665063 with human and mouse seeds. This is a supported regulatory role that follows from KRIT1 junctional organization, so it is kept as non-core rather than as a core molecular function. IBA, IEA and IMP rows are judged together. Supporting Evidence: PMID:20332120 In the absence of any of these proteins, AJs are dismantled, cell polarity is lost PMID:20332120 The protein interacts with VEC and directs AJ organization and AJ association with the polarity complex
GO:2000352 negative regulation of endothelial cell apoptotic process	IMP PMID:20616044 Cerebral cavernous malformation protein CCM1 inhibits sprout...	KEEP AS NON CORE	Summary: CCM1 depletion affects human endothelial apoptosis. Reason: Primary human endothelial cells depleted of CCM1 show increased proliferation, migration, apoptosis, lumen formation and sprouting (PMID:20616044). These quiescence-maintaining effects are real and consistent with the IBA/IMP rows for negative regulation of angiogenesis, but they are downstream outputs of the junctional Rap1-effector and adaptor activities (via DLL4-NOTCH and MEKK3 restraint), so they are kept as non-core. Supporting Evidence: PMID:20616044 CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells.
GO:0035024 negative regulation of Rho protein signal transduction	IMP PMID:21633110 A mechanism of Rap1-induced stabilization of endothelial cel...	NEW	Summary: Junction-localized KRIT1 suppresses Rho kinase signaling. Reason: Rap1-dependent junctional KRIT1 suppresses Rho kinase signaling (PMID:21633110), and a HEG1-binding-defective KRIT1 fails to complement the effect of KRIT1 depletion on Rho kinase activation in endothelial cells (PMID:23007647). KRIT1 is itself the regulator: it is the junctional effector whose presence restrains RhoA/ROCK, not a substrate of the pathway. Comparator check: the two other junctional members of this HEG1-Rap1 module, HEG1 (IMP) and RASIP1 (IMP, IBA), carry this same term in GOA, whereas KRIT1 lacks it. Supporting Evidence: PMID:21633110 Rap1 binding released KRIT1 from microtubules, enabling it to locate to cell--cell junctions, where it suppressed Rho kinase signaling and stabilized the junctions PMID:23007647 maintains junctional integrity in part by inhibiting RhoA

Gene Description

Existing Annotations Review

Core Functions

Rap1 effector: KRIT1 binds GTP-loaded Rap1 through its FERM F1/F2 lobes, which releases it from microtubules and recruits it to junctional plasma membrane, where it stabilizes endothelial cell-cell junctions.

Junctional adaptor of the CCM complex: the KRIT1 FERM domain binds the HEG1 cytoplasmic tail while its NPX(Y/F) motifs bind the CCM2 PTB domain, linking the KRIT1-CCM2-PDCD10 complex to endothelial junctions and restraining RhoA/Rho kinase signaling.

Membrane and microtubule binding that controls KRIT1 availability: KRIT1 binds microtubules through its N and C termini and binds PI(4,5)P2-containing membranes in a Rap1-enhanced manner.

ICAP1 sequestration: KRIT1 binds ICAP1 by a bidentate surface and competes with the beta1 integrin tail, relieving ICAP1-mediated suppression of integrin activation.

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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