PARD6G

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0060341 regulation of cellular localization	IBA GO_REF:0000033	ACCEPT	Summary: PAR6 proteins regulate the localization of polarity substrates through the PAR3-PAR6-aPKC complex. aPKC phosphorylates substrates like LGL, driving their exclusion from the apical membrane domain (Earl et al. 2025, vargas2023). The IBA annotation is consistent with the conserved role of PAR6 family members in controlling cellular localization of polarity determinants. Reason: The PAR6-aPKC complex controls the subcellular localization of polarity substrates through phosphorylation-dependent mechanisms. PARD6G as a scaffold regulates where aPKC acts, thereby regulating cellular localization of downstream targets. This is a core function. Supporting Evidence: PMID:39762628 Although aPKC-Par6 phosphorylates Lgl at three serine sites to exclude it from the apical domain, aPKC-Par6 and Lgl paradoxically form a stable kinase-substrate complex, with conflicting roles proposed for Par6. PMID:39762628 Mutational disruption of the Lgl-aPKC interaction impedes complex assembly and Lgl phosphorylation, whereas disrupting the Lgl-Par6PDZ contact promotes complex dissociation and Lgl phosphorylation.
GO:0007163 establishment or maintenance of cell polarity	IBA GO_REF:0000033	ACCEPT	Summary: Cell polarity establishment is the defining function of the PAR protein family. PARD6G as part of the PAR3-PAR6-aPKC complex is essential for establishing and maintaining apicobasal polarity in epithelial cells (PMID:11257119, PMID:11260256). Reason: This is the core, defining function of PARD6G. The PAR6 proteins are named for their role in partitioning defective mutants that disrupt cell polarity. The annotation is at an appropriate level of specificity for the general polarity function. Supporting Evidence: PMID:11260256 Human PAR6 homologues most likely play an important role in the cell polarization of mammalian cells, by functioning as an adaptor protein that links activated Rac and Cdc42 to aPKC signalling PMID:11257119 aPKC is critically involved in the development of the epithelial junctional structures and controls the cell polarity of mammalian epithelial cells, probably by forming a ternary complex with ASIP/PAR-3 and PAR-6
GO:0005938 cell cortex	IBA GO_REF:0000033	ACCEPT	Summary: PAR6 proteins localize to the cell cortex, particularly the apical cortex in polarized epithelial cells, where they function with aPKC to establish polarity domains. Reason: Cell cortex localization is consistent with the apical membrane localization where the PAR complex functions. The IBA annotation reflects conserved localization across PAR6 orthologs. Supporting Evidence: file:human/PARD6G/PARD6G-deep-research-falcon.md At the apical cortex, aPKC phosphorylates and excludes basolateral substrates (e.g., LGL), reinforcing apico-basal polarity
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Nuclear localization of PAR6 proteins is not a well-characterized aspect of PARD6G function. The primary functional localization is at the cell cortex, tight junctions, and plasma membrane. Reason: While nuclear localization may occur based on phylogenetic inference, the primary and best-characterized localization of PARD6G is at the cell cortex and tight junctions. Nuclear localization, if it occurs, does not appear to be central to the polarity function.
GO:0016324 apical plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: PAR6 proteins, as part of the PAR3-PAR6-aPKC complex, localize to the apical plasma membrane domain where they establish and maintain apical identity (vargas2023, Earl et al. 2025). Reason: Apical plasma membrane localization is a core aspect of PARD6G function. The PAR complex localizes to the apical cortex and tight junctions to establish apical-basal polarity. Supporting Evidence: file:human/PARD6G/PARD6G-deep-research-falcon.md CDC42-GTP engagement of PAR-6 CRIB-PDZ promotes apical membrane recruitment and tight-junction enrichment of the Par6-aPKC module
GO:0007098 centrosome cycle	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Centrosome cycle involvement is inferred phylogenetically but not extensively characterized for PARD6G specifically. PAR proteins have been implicated in asymmetric cell division which involves centrosome dynamics. Reason: While PAR proteins are involved in asymmetric cell division (which involves centrosomes), the centrosome cycle is not the primary characterized function of PARD6G. The core function is epithelial cell polarity at tight junctions.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: General cytoplasmic localization is consistent with UniProt annotation and the known biology of PAR6 proteins which shuttle between cytoplasm and membrane. Reason: Cytoplasmic localization is a valid general annotation. PARD6G is found in the cytoplasm and also at the plasma membrane/tight junctions. This IEA annotation from UniProt subcellular location is appropriate.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: Plasma membrane localization is consistent with the function of PARD6G at the apical plasma membrane domain where it functions in the PAR polarity complex. Reason: Plasma membrane localization is well-supported. The IEA annotation from UniProt subcellular location mapping is consistent with the known biology.
GO:0005923 bicellular tight junction	IEA GO_REF:0000044	ACCEPT	Summary: Tight junction localization is a core aspect of PARD6G function in epithelial cells. The PAR3-PAR6-aPKC complex localizes to tight junctions (PMID:11257119). Reason: Tight junction localization is well-documented and central to PARD6G function in epithelial polarity. This annotation is appropriate. Supporting Evidence: PMID:11257119 in mammalian epithelial cells that exhibit well-developed apico-basal cell polarity, ASIP/PAR-3 concentrate at the tight junction (TJ) together with aPKC
GO:0051301 cell division	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: Cell division annotation is derived from UniProt keyword mapping. PAR proteins were originally identified for their role in asymmetric cell division in C. elegans embryos. Reason: While PAR proteins are involved in asymmetric cell division (the original discovery context in C. elegans), the primary characterized function of human PARD6G is in epithelial cell polarity and tight junction organization. Cell division is not the core function in epithelial contexts.
GO:0005515 protein binding	IPI PMID:11260256 Human homologues of the Caenorhabditis elegans cell polarity...	REMOVE	Summary: This annotation refers to binding to CDC42, RAC1, PRKCI, and PRKCZ demonstrated by Noda et al. 2001. The PAR6 proteins interact with GTP-bound Rac and Cdc42 via the CRIB motif and with aPKC isoforms via PB1 domain interaction. Reason: While the underlying interaction data is valid, GO:0005515 (protein binding) is uninformative. The specific binding activities should be annotated with more informative terms such as GO:0031267 (small GTPase binding) for CDC42/RAC1 binding and GO:0005080 (protein kinase C binding) for PRKCI/PRKCZ binding. Proposed replacements: small GTPase binding protein kinase C binding Supporting Evidence: PMID:11260256 PAR6 proteins harbour a PDZ domain and a CRIB-like motif, and directly interact with GTP-bound Rac and Cdc42 via this motif and with the aPKC isoforms PKCiota/lambda and PKCzeta via the N-terminal head-to-head association
GO:0005515 protein binding	IPI PMID:14676191 Comprehensive proteomic analysis of human Par protein comple...	REMOVE	Summary: This annotation is from a comprehensive proteomic analysis of human Par protein complexes by Brajenovic et al. 2004, which identified novel interactors of the Par complex network including 14-3-3 proteins. Reason: GO:0005515 (protein binding) is too general and uninformative for this adaptor/scaffold protein. The specific molecular functions (adaptor activity, kinase binding) are more appropriate annotations. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:14676191 2003 Dec 15. Comprehensive proteomic analysis of human Par protein complexes reveals an interconnected protein network.
GO:0005515 protein binding	IPI PMID:17057644 A distinct PAR complex associates physically with VE-cadheri...	REMOVE	Summary: This annotation refers to PAR complex interactions with VE-cadherin in endothelial cells (Iden et al. 2006). The study found PAR-3 and PAR-6 associate with VE-cadherin. Reason: GO:0005515 is uninformative. While the interaction with VE-cadherin is interesting, the general protein binding term does not capture the specific adaptor function. Supporting Evidence: PMID:17057644 A distinct PAR complex associates physically with VE-cadherin in vertebrate endothelial cells.
GO:0005515 protein binding	IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo...	REMOVE	Summary: This reference is about integrative analysis of kinase networks in TRAIL-induced apoptosis, which is not directly related to the core polarity function of PARD6G. Reason: GO:0005515 is uninformative for an adaptor protein. High-throughput interaction data should be annotated with more specific terms when the molecular function is known. Supporting Evidence: PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	REMOVE	Summary: This reference describes architecture of the human interactome. This is high-throughput interaction data that does not add specific functional information beyond what is already known about PARD6G interactions. Reason: GO:0005515 is uninformative. High-throughput interactome data should not result in uninformative protein binding annotations when the specific molecular function is already known (adaptor/scaffold activity). Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	REMOVE	Summary: This reference is about EGFR network rewiring in KRAS-mutant colorectal cancer cells. Not directly related to the core polarity function of PARD6G. Reason: GO:0005515 is uninformative and the context (KRAS-mutant cancer network rewiring) does not reflect core PARD6G function. Supporting Evidence: PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
GO:0005515 protein binding	IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro...	REMOVE	Summary: This reference is about kinase interaction networks expanding functional and disease roles. High-throughput data that does not add specific functional information. Reason: GO:0005515 is uninformative for an adaptor protein whose specific binding partners and molecular function are well characterized. Supporting Evidence: PMID:32707033 2020 Jul 23. Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: This reference is about dual proteome-scale networks revealing cell-specific interactome remodeling. High-throughput data. Reason: GO:0005515 is uninformative. For PARD6G, the more specific adaptor activity and specific binding terms are more appropriate. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0070160 tight junction	NAS PMID:11257119 Atypical protein kinase C is involved in the evolutionarily ...	ACCEPT	Summary: Tight junction localization is well-supported by PMID:11257119 (Suzuki et al. 2001) which showed that aPKC, PAR-3, and PAR-6 localize to the tight junction in epithelial cells. Reason: Tight junction localization is a core aspect of PARD6G function. The reference clearly demonstrates TJ localization of the PAR complex. Supporting Evidence: PMID:11257119 mammalian PAR-6 localizes to the apical junctional region together with aPKC and ASIP/PAR-3
GO:0005829 cytosol	TAS Reactome:R-HSA-419981	ACCEPT	Summary: Cytosolic localization is part of the dynamic localization of PAR6 proteins, which shuttle between cytosol and membrane during polarity establishment. Reason: Cytosolic localization is consistent with the known biology of PAR6 proteins. The Reactome pathway annotation for tight junction recruitment is appropriate.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-419981	ACCEPT	Summary: Plasma membrane localization is supported by the Reactome pathway for recruitment of PAR-3:PAR-6:aPKC complex to tight junctions. Reason: Plasma membrane localization is well-supported and central to PARD6G function. This is a duplicate of the IEA annotation but from Reactome pathway evidence.
GO:0035591 signaling adaptor activity	IDA PMID:11260256 Human homologues of the Caenorhabditis elegans cell polarity...	NEW	Summary: PARD6G functions as a signaling adaptor that links GTP-bound Rho GTPases (CDC42, RAC1) to aPKC, enabling coordinated signaling in cell polarity pathways. This is the core molecular function of PAR6 proteins. Reason: This annotation captures the core molecular function of PARD6G as demonstrated by Noda et al. 2001. The protein functions as an adaptor bringing together CDC42/RAC1 and aPKC in a ternary complex for polarity signaling. Supporting Evidence: PMID:11260256 Human PAR6 homologues most likely play an important role in the cell polarization of mammalian cells, by functioning as an adaptor protein that links activated Rac and Cdc42 to aPKC signalling
GO:0031267 small GTPase binding	IPI PMID:11260256 Human homologues of the Caenorhabditis elegans cell polarity...	NEW	Summary: PARD6G directly binds GTP-bound forms of CDC42 and RAC1 via its CRIB-PDZ domain. This interaction is essential for recruiting the PAR complex to sites of polarization. Reason: This is a more informative annotation than GO:0005515 for the demonstrated binding to CDC42 and RAC1. The CRIB domain mediates this interaction. Supporting Evidence: PMID:11260256 The PAR6 proteins harbour a PDZ domain and a CRIB-like motif, and directly interact with GTP-bound Rac and Cdc42 via this motif
GO:0005080 protein kinase C binding	IPI PMID:11260256 Human homologues of the Caenorhabditis elegans cell polarity...	NEW	Summary: PARD6G binds aPKC isoforms (PRKCI and PRKCZ) via its PB1 domain. This PB1-PB1 heterodimerization is essential for formation of the PAR polarity complex. Reason: This is a more informative annotation than GO:0005515 for the demonstrated binding to PRKCI and PRKCZ. The PB1 domain mediates this interaction. Supporting Evidence: PMID:11260256 The PAR6 proteins harbour a PDZ domain and a CRIB-like motif, and directly interact with GTP-bound Rac and Cdc42 via this motif and with the aPKC isoforms PKCiota/lambda and PKCzeta via the N-terminal head-to-head association file:human/PARD6G/PARD6G-deep-research-falcon.md PAR-6 proteins are polarity adaptors with an N-terminal PB1 domain that heterodimerizes with the PB1 of aPKC
GO:0120157 PAR polarity complex	ISS PMID:11257119 Atypical protein kinase C is involved in the evolutionarily ...	NEW	Summary: PARD6G is a core component of the PAR polarity complex together with PARD3 and aPKC. This complex is essential for establishing cell polarity. Reason: This cellular component annotation is appropriate as PARD6G is a defining member of the PAR polarity complex. ComplexPortal entries CPX-6194 and CPX-6195 document PARD6G-containing PAR complexes. Supporting Evidence: PMID:11257119 we also found that aPKC associates not only with ASIP/PAR-3, but also with a mammalian homologue of C. elegans PAR-6
GO:0045197 establishment or maintenance of epithelial cell apical/basal polarity	ISS PMID:11257119 Atypical protein kinase C is involved in the evolutionarily ...	NEW	Summary: PARD6G as part of the PAR complex is essential for establishing apicobasal polarity in epithelial cells. This is more specific than the general cell polarity term. Reason: This is a more specific biological process annotation than GO:0007163 that captures the epithelial-specific function of PARD6G in apicobasal polarity. Supporting Evidence: PMID:11257119 aPKC is critically involved in the development of the epithelial junctional structures and controls the cell polarity of mammalian epithelial cells file:human/PARD6G/PARD6G-deep-research-falcon.md aPKC phosphorylates and excludes basolateral substrates (e.g., LGL), reinforcing apico-basal polarity

Gene Description

Existing Annotations Review

Core Functions

Signaling adaptor/scaffold activity in the PAR polarity complex, linking activated Rho GTPases (CDC42, RAC1) to atypical protein kinase C (aPKC) for coordinated polarity signaling.

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