Overview of PARD6G and the PAR6 Family OpenAI o3-deep-research-2025-06-26 176 citations 2025-12-27T18:18:23.103525

Overview of PARD6G and the PAR6 Family

PARD6G (Par6γ) is a human gene encoding the partitioning-defective 6 homolog gamma protein, also called PAR6 gamma or PAR6D (www.ncbi.nlm.nih.gov). It belongs to the PAR6 family of polarity-regulating adapter proteins, which were first identified in C. elegans as key determinants of asymmetric cell division (the “partitioning-defective” genes) (en.wikipedia.org). Like other PAR6 isoforms (Par6α/PARD6A and Par6β/PARD6B), the Par6γ protein contains several conserved domains: an N-terminal PB1 (OPR) domain, a PDZ domain, and a semi-CRIB domain (en.wikipedia.org). The PB1 domain (Phox/Bem1-type) mediates heterodimerization with other PB1-domain proteins (notably the atypical PKC kinases), while the PDZ domain (PSD95/Discs-large/ZO-1) enables Par6 to scaffold with partners like PAR3 (v21.proteinatlas.org). The “semi-CRIB” region (Cdc42/Rac interactive binding) allows Par6γ to bind active Rho family GTPases (e.g. Cdc42 and Rac1) (en.wikipedia.org). Through these modules, PARD6G’s protein product functions as an adaptor/scaffold that links small GTPases (Cdc42/Rac) to atypical PKC (aPKC) kinases within larger polarity complexes (v21.proteinatlas.org). This molecular architecture is central to its role in cell polarity and signaling.

Key Functional Definition: Par6γ is a regulatory scaffold protein involved in establishing cell polarity and oriented cell division. According to UniProt/Swiss-Prot and expert databases, PARD6G is “an adapter protein involved in asymmetrical cell division and cell polarization processes”, potentially playing a role in forming epithelial tight junctions (v21.proteinatlas.org) (www.genecards.org). In essence, Par6γ does not act as an enzyme or structural filament itself; rather, it organizes signaling complexes at specific cell locations. By binding partners like PAR3 (PARD3) and aPKC, Par6γ helps define the apical membrane domain of epithelial cells and links polarity cues from Rho GTPases to downstream effectors (v21.proteinatlas.org). This function is conserved across species – for example, a seminal Nature Cell Biology study demonstrated that Par6 proteins bridge PAR3 and aPKC to the GTP-bound form of CDC42, anchoring the kinase to precise cortical sites (en.wikipedia.org). Through such interactions, Par6γ orchestrates where and when aPKC phosphorylates targets, thereby guiding processes like junction assembly, cytoskeletal reorganization, and cell-fate asymmetry. In summary, PARD6G encodes a polarity complex scaffold critical for proper cellular orientation and signaling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Domain Structure and Molecular Interactions

Par6γ’s multi-domain structure enables specific protein–protein interactions that underlie its scaffolding function. At the N-terminus, Par6γ contains a PB1 domain (also known historically as an OPR domain) (en.wikipedia.org). This PB1 domain allows Par6γ to heterodimerize with the PB1 domains of atypical PKC isoforms (such as PKCζ or PKCλ/ι) (en.wikipedia.org). Through PB1-mediated binding, Par6γ directly tethered aPKC to the polarity complex, regulating its localization and activity. The PB1 interaction is critical: disrupting the PB1 domain prevents Par6 from binding aPKC and impairs polarity signaling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). For instance, in zebrafish pard6γb mutants, restoring the PB1 (aPKC-binding) domain is essential to rescue normal function in neural tube development (pmc.ncbi.nlm.nih.gov).

Adjacent to the PB1 domain, Par6γ harbors a PDZ domain, a modular interaction domain commonly binding C-terminal motifs of partner proteins. In the canonical Par polarity complex, Par6’s PDZ domain binds a C-terminal PDZ-binding motif of PAR3 (another partitioning-defective protein) (en.wikipedia.org). This PDZ-mediated link is what couples Par6γ (with aPKC attached) to the PAR3 scaffold at the cell cortex. Notably, Par6 PDZ domains can also engage other polarity factors – for example, Par6 can connect to the Crumbs/PALS1/PATJ complex via a PDZ-binding motif (the KPLG sequence) that binds PALS1 (MPP5) (pmc.ncbi.nlm.nih.gov). This ability to interface with the Crumbs complex underscores Par6γ’s central role coordinating multiple polarity modules. Finally, Par6γ includes a semi-CRIB domain (a partial Cdc42/Rac interactive binding sequence) overlapping the PDZ or C-terminus (en.wikipedia.org). This region specifically binds the active (GTP-bound) forms of Rho-family GTPases like CDC42, RAC1, and related proteins (e.g. TC10/RhoQ) (en.wikipedia.org). Through this interaction, Par6γ is recruited to sites of active CDC42 at the cell membrane, which often mark the nascent apical pole or leading edge of the cell (en.wikipedia.org). The Par6γ–CDC42 interaction is pivotal for polarity signaling – it essentially links external or upstream polarity cues (small GTPase activation) to the assembly of the PAR3/PAR6/aPKC complex at the correct location (v21.proteinatlas.org). In support of this, mutational analyses in model organisms have shown that the CRIB (CDC42-binding) motif of Par6γ is required for its function in epithelial morphogenesis (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Key molecular partners of Par6γ include:
- PAR3 (PARD3) – a scaffold protein that localizes to tight junctions and cell cortex; Par6γ’s PDZ domain binds PAR3, linking Par6γ–aPKC to PAR3’s complex (v21.proteinatlas.org).
- aPKC (PKCζ, PKCλ/ι) – atypical protein kinase C isoforms; Par6γ’s PB1 domain forms a heterodimer with aPKC PB1, anchoring the kinase into the Par complex (v21.proteinatlas.org). This interaction positions aPKC to phosphorylate downstream targets (such as PAR3 or lateral domain proteins) and is essential for polarity establishment.
- CDC42 and RAC1 – small Rho-family GTPases; GTP-bound CDC42 or Rac1 directly bind Par6γ (via the CRIB region), recruiting the Par6γ–PAR3–aPKC complex to specific membrane locales (en.wikipedia.org). Active CDC42 effectively “activates” the Par complex; in many systems, CDC42-Par6 binding relieves an autoinhibition of aPKC, triggering localized kinase activity (en.wikipedia.org). This is crucial for events like asymmetric cell division (e.g., polarizing the mitotic spindle) and leading edge dynamics in migrating cells.
- RhoQ (TC10) – another Rho GTPase; Par6γ (like Par6β) can also interact with TC10, suggesting broad binding to several polarity-related GTPases (en.wikipedia.org).
- PALS1 (MPP5) and Crumbs – via Par6γ’s PDZ domain motif (KPLG in Par6γ), it can bind PALS1, which in turn connects to Crumbs, integrating the PAR complex with the Crumbs polarity complex at apical junctions (pmc.ncbi.nlm.nih.gov). This crosstalk is important for tight junction formation and apical membrane identity.
- Other partners: Par6 proteins have been reported to interact with additional signaling molecules. For example, Par6α can bind ECT2 (a RhoGEF) (en.wikipedia.org), linking polarity to regulation of RhoA. Par6γ’s interactome is less characterized in literature, but by homology it may share many interactors with Par6α/β. All Par6 isoforms also indirectly influence cytoskeletal and junctional proteins (E-cadherin, actin regulators) through the aPKC pathway.

Through these interactions, Par6γ acts as a hub, assembling a multi-protein complex (often termed the PAR complex) at the cell cortex (pmc.ncbi.nlm.nih.gov). The integrity of this complex is required for downstream signaling – for instance, if Par6γ fails to recruit aPKC or bind CDC42, the cell cannot properly establish or maintain polarity (pmc.ncbi.nlm.nih.gov). In summary, the domains of Par6γ endow it with the ability to couple the signals from Rho GTPases to the execution machinery of cell polarity (PAR3–aPKC and the actin/tubulin cytoskeleton) (en.wikipedia.org) (pmc.ncbi.nlm.nih.gov). This molecular scaffolding function is fundamental to the biological roles described next.

Role in Cell Polarity and Biological Processes

Par6γ is a core component of the evolutionarily conserved PAR polarity complex, which is essential for a variety of cellular polarization events. In epithelial cells, Par6γ (together with Par3 and aPKC) governs apical–basal polarity, the process by which the “top” (apical surface) and “bottom” (basal surface) of the cell acquire distinct compositions and functions (pmc.ncbi.nlm.nih.gov). The Par3/Par6/aPKC complex localizes to the apical cortex at sites of cell–cell contact, just above the tight junctions (which separate apical and lateral surfaces) (www.ncbi.nlm.nih.gov). By recruiting aPKC to the apical junctional region, Par6γ helps establish the apical membrane domain and promotes the maturation of tight junctions (www.genecards.org) (v21.proteinatlas.org). Experimental evidence shows that loss of Par6 function disrupts tight junction assembly: for example, RNAi knockdown of PARD6 homologs can prevent proper localization of junctional markers and cause epithelial layer disorganization (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Indeed, Par6γ is predicted (from Gene Ontology data and homology) to be active at tight junctions, the apical plasma membrane, and the cell cortex in polarized epithelial cells (www.ncbi.nlm.nih.gov). High-resolution imaging confirms Par6 proteins concentrate at the plasma membrane of cells, especially in polarized epithelia (e.g. at the apical cell–cell contacts) (v21.proteinatlas.org). The Human Protein Atlas identifies PARD6G as localized predominantly to the plasma membrane in human cells (v21.proteinatlas.org), consistent with its role in cortical polarity complexes.

Asymmetric cell division is another key process involving Par6γ. As cells divide, the PAR complex can become enriched on one side of the cell, biasing the mitotic spindle orientation and fate determinants into one daughter cell. Par6γ’s role in this was first exemplified in model organisms: in the one-cell C. elegans embryo, for instance, Par6 (with Par3-aPKC) localizes to the anterior cortex and is indispensable for unequal partitioning of cell-fate factors (www.sciencedirect.com). In mammals, Par6 proteins similarly regulate spindle orientation in stem cells and epithelia. A striking example comes from zebrafish: mutants lacking Pard6γb (a zebrafish homolog of PARD6G) show misoriented spindles during neurulation and abnormal tissue morphology (pmc.ncbi.nlm.nih.gov). Specifically, Pard6γb mutant embryos failed to maintain a single central lumen in the neural tube, instead forming multiple lumens due to loss of coordinated apical polarity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These defects were tied to disrupted apical membrane formation and spindle misorientation – cells lacking Pard6γb could not properly align their division axis, linking Par6 to the centrosome/spindle positioning process (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Consistently, PARD6G is annotated to be involved in the centrosome cycle and regulation of cellular localization, according to predictive databases (www.ncbi.nlm.nih.gov). The ability of Par6γ to influence mitotic spindle orientation is a direct consequence of its polarity function: by defining an apical domain, Par6 (and associated proteins like LGN/NuMA in some systems) helps guide the mitotic apparatus for asymmetric outcome.

Apical domain assembly and cell morphogenesis: Par6γ’s presence is crucial for forming specialized apical structures. In epithelial morphogenesis assays (3D cultures of mammary cells), PARD6G was identified as a necessary gene for normal acinar architecture (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). When PARD6G was silenced in non-transformed mammary organoids, cells failed to exit the cell cycle on schedule and the spherical acinar structures became enlarged and disorganized (pmc.ncbi.nlm.nih.gov). In other words, Par6γ loss led to uncontrolled growth and loss of the symmetric architecture of the epithelial acini (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This phenotype underscores Par6γ’s role in coupling cell polarity to growth arrest and organized tissue structure. Likewise, in zebrafish pard6γb mutants, epithelial tissues like the neural tube and kidneys exhibited polarity defects (e.g. multi-lumen tubules) and differentiation issues (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Altogether, these findings demonstrate that Par6γ is indispensable for maintaining epithelial integrity and architecture, by establishing apico-basal polarity which in turn influences cell proliferation and tissue organization. Par6γ’s involvement extends to neurodevelopment as well: Par3/Par6/aPKC complexes guide processes such as neuronal migration, neurite outgrowth, and synaptic development (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). For example, during neuronal polarization, Par6 (with aPKC) accumulates in the budding axon of a neuron, helping one neurite differentiate into the axon while others become dendrites (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Disruption of Par6 function in neural progenitors can lead to neurodevelopmental defects and has been implicated in neuropsychiatric disorders, emphasizing that its polarity-regulating role is vital in many contexts beyond epithelia (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Cellular localization: Par6γ is an intracellular protein that mainly functions at the cell periphery. It is found in the cytosol and cortical regions of cells, often concentrated where cell-cell or cell-substrate contacts form (www.ncbi.nlm.nih.gov). Par6γ is strongly enriched at the apical cortex in polarized cells – e.g., at the apical junction complex of epithelial cells (where tight junctions reside) (www.ncbi.nlm.nih.gov). Given its binding to membrane-associated small GTPases and to PAR3 (which itself binds junctional adhesion proteins), Par6γ effectively attaches to the plasma membrane at specific spots. The protein has also been detected in other compartments under certain conditions: for instance, large-scale cell atlas projects list Par6γ as present in the nucleus as well (www.ncbi.nlm.nih.gov), though the functional significance of any nuclear pool is not well understood. It’s possible that a fraction of Par6γ (or specific isoform splice variants) shuttle to the nucleus or that overexpression can reveal nuclear localization, but the predominant functional locale is the cell cortex and membrane. In summary, Par6γ carries out its role at the cell periphery – at plasma membrane sites, particularly the apical membrane and junctional regions in polarized cells (www.ncbi.nlm.nih.gov) (v21.proteinatlas.org). This localization is consistent with its job as a polarity scaffold, positioning signaling enzymes and structural proteins at the correct cellular address.

Signaling Pathways and Mechanisms Involving Par6γ

Par6γ functions as a node in multiple signaling pathways that govern cell polarity, cell cycle, and cytoskeletal dynamics. One well-characterized pathway is its interplay with the Rho GTPase signaling cascade. Par6γ, via its CRIB domain, binds activated Cdc42 or Rac1 at the membrane (en.wikipedia.org). This positions Par6γ–aPKC at sites of active Cdc42. Cdc42 is often upstream of polarity establishment; for example, in migrating cells, a Cdc42-Par6-aPKC complex helps define the front of the cell. In epithelia, Cdc42 localized at the developing apical surface recruits Par6/aPKC to initiate apical membrane formation. When Cdc42 binds Par6, it can induce conformational changes that modulate aPKC activity. In fact, Cdc42’s role in Par complex activation is conserved from fly to human: loss of Cdc42 phenocopies loss of Par6 in causing polarity defects (pubmed.ncbi.nlm.nih.gov). Thus, Par6γ is a critical effector of Cdc42, translating Cdc42’s spatial cues into assembly of polarity complexes and targeted phosphorylation events.

Atypical PKC signaling: Once localized by Par6γ, aPKC phosphorylates a suite of substrates that execute polarization. For instance, aPKC can phosphorylate PAR3 (causing PAR3 to dissociate from the tight junction, refining the complex’s composition) and can phosphorylate lateral domain proteins like LGL (Lethal giant larvae) to exclude them from the apical cortex (www.sciencedirect.com). This creates mutually exclusive membrane domains – an apical region with Par3/Par6/aPKC, and a basolateral region with other complexes – establishing polarity. By scaffolding aPKC, Par6γ indirectly controls such phosphorylation events. If Par6γ is absent or not at the membrane, aPKC may mislocalize or remain inactive, leading to polarity loss. The Par6γ–aPKC module is also involved in junctional dynamics and actin remodeling. One notable mechanism is seen during epithelial–mesenchymal transition (EMT) triggered by TGF-β signaling: Par6 (likely Par6α/β in these studies) gets phosphorylated by the TGF-β type II receptor, which enables Par6 to recruit the E3 ubiquitin ligase Smurf1 (www.sciencedirect.com). The Par6–Smurf1 complex then targets the small GTPase RhoA for degradation, causing localized loss of actomyosin contractility at tight junctions (www.sciencedirect.com). This results in the dissolution of tight junctions and loss of apical polarity, a critical early step in EMT when epithelial cells become migratory. In summary, Par6 acts as a key mediator in TGF-β/Smurf1 signaling to downregulate RhoA and promote junction disassembly during EMT (www.sciencedirect.com). This illustrates how Par6γ can integrate with broader signaling networks (here, integrating a growth factor signal to a polarity/cytoskeleton outcome).

Beyond TGF-β, Par6γ influences cell cycle regulatory signaling. Recent research has uncovered a connection between the Par6 complex and the PI3K/Akt pathway, which is a major cell growth and survival signaling cascade. In a 3D mammary epithelial model, loss of PARD6G was found to cause aberrant activation of protein kinase B (Akt), a central growth regulator (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Specifically, PARD6G knockdown led to sustained phosphorylation of Akt at its activating sites (Thr308 and Ser473) even under growth factor–deprived conditions (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This was linked to the canonical PI3K–PDK1–Akt pathway: without Par6γ, phosphorylation of Akt by PDK1 was unchecked, resulting in hyperactive Akt signaling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Mechanistically, Par6γ loss also reduced phosphorylation of PKCζ at its activation loop (pmc.ncbi.nlm.nih.gov), indicating that the Par complex’s activity was compromised. Since aPKC is known to scaffold with and be regulated by PDK1 as well, one hypothesis is that Par6γ normally sequesters or regulates PDK1–aPKC interactions, thereby indirectly restraining Akt activation (Akt requires PDK1 and PIP₃ to be fully active) (pmc.ncbi.nlm.nih.gov). In the absence of Par6γ, PDK1 may more freely activate Akt, bypassing normal polarity-coupled growth suppression. In essence, Par6γ serves as a brake on the PI3K/Akt pro-growth pathway, coupling epithelial structure to cell cycle exit (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This concept is supported by functional studies: cells lacking Par6γ failed to undergo normal cell cycle arrest in 3D culture, but when researchers inhibited PDK1 (upstream of Akt), the uncontrolled proliferation caused by Par6γ loss was partly rescued (pmc.ncbi.nlm.nih.gov). Thus, Par6γ exerts a tumor-suppressive signal by negatively regulating Akt activity via the PAR complex integrity. This finding places Par6γ at an intersection of polarity signaling and classical growth factor signaling.

Other pathways: Par6γ (and its relatives) have been implicated in additional signaling contexts. For example, in neuronal cells, Par6–aPKC can interact with GSK-3β and adenomatous polyposis coli (APC) to regulate microtubule dynamics during axon specification (pmc.ncbi.nlm.nih.gov). In endothelial cells, Par6 is involved in VEGF signaling to modulate cell migration and lumen formation. The Hippo pathway – an important regulator of organ size and growth – is functionally tied to cell polarity proteins as well; disruptions in Par6 can affect Hippo signaling by mislocalizing Hippo components at the cortex (pmc.ncbi.nlm.nih.gov). Indeed, a screen of epithelial structure regulators found that Par6γ and the Hippo kinases both contribute to restricting growth in organoids (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These examples emphasize that Par6γ’s influence extends into many biochemical pathways by virtue of its ability to organize protein complexes at specific cell locations and times. Whenever cell architecture needs to be coordinated with signaling (be it during development, wound healing, or cell migration), Par6γ is often one of the key orchestrators.

Clinical and Real-World Implications of PARD6G Function

Par6γ’s role as a polarity regulator has significant implications in development and disease. Particularly in cancer biology, cell polarity proteins can act as context-dependent tumor suppressors or promoters (pmc.ncbi.nlm.nih.gov). In normal epithelial tissue, proper polarity (organized by Par6γ complexes) keeps cell growth in check and maintains tissue architecture. Loss of polarity is a hallmark of high-grade tumors – cancer cells often exhibit disorganized architecture and uncontrolled proliferation. Given Par6γ’s function in enforcing growth arrest when epithelial structure is intact, it is perhaps not surprising that PARD6G appears to function as a tumor suppressor in certain contexts (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Large-scale cancer genome analyses show that the PARD6G gene is frequently inactivated in multiple epithelial cancers (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In one study analyzing data from The Cancer Genome Atlas and other datasets, PARD6G was found to undergo loss-of-function alterations (chromosomal deletions, loss of heterozygosity, or inactivating mutations) in diverse tumor types, whereas its sister gene PARD6B more often showed amplifications or overexpression in cancers (pmc.ncbi.nlm.nih.gov). This dichotomy suggests that elevated Par6β might benefit some tumors (potentially by aiding invasive behavior), while loss of Par6γ removes restraints on proliferation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The functional studies by Marques et al. support this: silencing PARD6G in mammary organoids led to hyper-proliferation and overgrowth, mimicking a neoplastic phenotype (pmc.ncbi.nlm.nih.gov). The same study reported that PARD6G knockdown alone could drive cells to continue cycling when they should be quiescent, whereas PARD6B knockdown required additional oncogenic signals (like MYC activation) to cause a similar effect (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These results position Par6γ as a stronger enforcer of normal growth limits. Consistently, active Akt signaling was observed in Par6γ-deficient cells even in the absence of growth factors, reinforcing the link between Par6γ loss and a pro-tumorigenic pathway (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). As the authors concluded, “Par6 activity appears to be important for repressive regulation of PI3K/PDK1/Akt-dependent proliferation”, and loss of Par6G unleashes AKT-driven growth signals (pmc.ncbi.nlm.nih.gov). In human tumors, this may translate to a selective pressure to delete or silence PARD6G in order to bypass polarity-dependent growth arrest. Indeed, the PARD6G gene was found to be frequently deleted or downregulated in certain cancers (e.g. subsets of breast, liver, and colon carcinomas) (pmc.ncbi.nlm.nih.gov). Supporting this, Oncogene database analyses (cBioPortal) have identified PARD6G mutations and deletions in patient tumors, consistent with its proposed tumor suppressor role (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). It is noteworthy that PARD6B, in contrast, is sometimes upregulated in cancers (for example, amplified in some colorectal cancers, as an oncogenic driver of MYC signaling) (pmc.ncbi.nlm.nih.gov). These divergent patterns indicate that therapies might need to consider isoform-specific contexts – inhibiting Par6β pathways where it’s oncogenic, while somehow restoring or mimicking Par6γ’s function where its loss drives cancer.

In terms of real-world clinical relevance, polarity proteins like PARD6G are being studied as both biomarkers and therapeutic targets. As a biomarker, loss of PARD6G expression or function might correlate with cancer progression. For instance, analysis from the Human Protein Atlas notes that high PARD6G expression is an unfavorable prognostic marker in liver cancer patients (v21.proteinatlas.org) (this could reflect a subset of tumors where Par6γ upregulation is associated with more aggressive behavior, or perhaps a feedback response in advanced disease; the exact interpretation is still under investigation). Conversely, the absence of Par6γ might mark tumors with a loss of polarity. On the therapeutic front, one strategy is to target the Par6–aPKC interaction in cancers where it’s pathologically activated. In certain aggressive cancers (e.g. some melanomas and breast carcinomas), an atypical PKC/Par6 pathway is hijacked to promote EMT and invasion (en.wikipedia.org). For example, in metastatic melanoma cells, PKC-ι (aPKC lambda/iota) forms a complex with Par6 that drives EMT and cell invasion; inhibiting PKC-ι was shown to reduce Par6 levels, restore E-cadherin at cell junctions, increase RhoA (which stabilizes junctions), and decrease vimentin, thereby reversing EMT markers (en.wikipedia.org). Two novel aPKC inhibitors tested in that context (ACPD and DNDA) effectively suppressed melanoma cell proliferation and EMT, inducing apoptosis (en.wikipedia.org). This indicates that disrupting the Par6–aPKC signaling axis can have anti-tumor effects in cancers dependent on that pathway. While those inhibitors target PKC, not Par6 directly, they underscore a wider concept: the Par6 polarity complex is actionable – it can be modulated to impact cell adhesion and migration in cancer. In the future, targeting Par6γ specifically could be challenging (as scaffold proteins lack easy drug-binding pockets), but understanding its pathway suggests alternative nodes to hit (like PKC-ι, or upstream regulators like TGF-β signaling in EMT contexts).

Another “real-world” application of PARD6G biology is in the field of organ-on-a-chip and 3D culture systems. Polarity proteins are used as readouts for proper tissue organization. In drug testing using organoids or spheroids, researchers often examine Par6/Par3 localization to ensure the model forms realistic architecture. Indeed, the identification of Par6γ as necessary for quiescent, growth-arrested acini in 3D culture (pmc.ncbi.nlm.nih.gov) suggests that measuring PARD6G expression or localization could inform whether an organoid has achieved a differentiated state. Similarly, in regenerative medicine, promoting proper expression of Par6γ might aid the formation of organized epithelial layers. Genetic studies in animals also underscore the physiological importance of PARD6G – for example, mouse models (Mus musculus Pard6g) may exhibit developmental defects if this gene is disrupted (though detailed mouse knockout phenotypes aren’t widely reported, likely due to redundancy with other isoforms). In zebrafish, as discussed, pard6γb mutants provided a real-world demonstration that loss of a Par6 gene leads to multi-lumen organs and polarity defects (pmc.ncbi.nlm.nih.gov). This has relevance to human congenital conditions: defects in cell polarity genes can contribute to developmental disorders and polycystic diseases (where tubules lose their single-lumen structure, somewhat reminiscent of the zebrafish phenotype).

Outside of pathology, PARD6G has been implicated in natural physiological variations and aging. A 2023 cross-species study on aging dogs found that PARD6G exhibits age-associated DNA methylation changes (pmc.ncbi.nlm.nih.gov). In older dogs, the PARD6G gene region was significantly hypomethylated compared to younger dogs (pmc.ncbi.nlm.nih.gov). Since hypomethylation often correlates with increased gene expression, this could suggest that Par6γ expression is upregulated with age, possibly as a response to cellular aging or as part of the aging process in tissues. The study further noted that many genes showing age-dependent methylation (including PARD6G) also have known roles in tumor suppression and differentiation control (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This raises an intriguing point: Par6γ sits at the crossroads of aging and cancer – its regulation might change with age in a way that impacts cancer risk or tissue integrity. In human data, the PARD6G locus also encodes a long non-coding RNA, PARD6G-AS1, which recent analyses have linked to cancer outcomes. For example, in endometrial cancer, hypomethylation of the PARD6G-AS1 lncRNA was associated with higher recurrence risk and metastasis (www.frontiersin.org) (www.frontiersin.org). While that finding pertains to an antisense RNA and not the protein itself, it highlights the broader significance of the PARD6G genomic region in disease. The authors of that 2024 study noted that “PAR6 proteins […] interact with classical cancer driver signaling pathways”, reinforcing that the Par6 family (including Par6γ) is embedded in critical oncogenic networks (www.frontiersin.org).

Expert perspectives: Authorities in cell polarity and cancer research have increasingly recognized PARD6G’s importance. A 2023 review in Life Sciences (Zhang et al.) dedicated to Par6 in tumor development emphasized that Par6 is a “core regulator of cell polarity whose dysregulation is increasingly implicated in tumorigenesis and progression.” (pubmed.ncbi.nlm.nih.gov). Notably, this review highlights the distinct expression patterns of Par6 isoforms (PARD6A, PARD6B, PARD6G) across different cancer types and their divergent clinical implications (pubmed.ncbi.nlm.nih.gov). In other words, experts acknowledge that Par6γ may behave differently from Par6α/β in disease contexts – an insight that matches the data showing Par6γ is lost in cancers whereas Par6β can be upregulated (pmc.ncbi.nlm.nih.gov). The same review elaborates on how Par6 proteins contribute to tumor biology, including interactions with pathways like TGF-β (for EMT), Notch, Wnt, and others that drive tumor progression (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Another commentary by Marques and Klefström (2015) succinctly noted that “many advances in polarity research may have flown under the radar of mainstream cancer biology,” but that recent findings (including their own) “suggest that loss of epithelial integrity and polarity can directly unleash proliferative signals” (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Their work essentially positions Par6G as a linchpin linking epithelial architecture to cell-cycle control, such that breaking polarity (via Par6G loss) removes a barrier to cancerous growth (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This paradigm is now gaining traction: maintaining cell polarity is seen as a non-canonical tumor suppressor mechanism (www.nature.com).

From a biomedical research standpoint, the PAR6G gene and its protein product are increasingly studied for their role in disease modeling and therapy. The evidence that Par6γ negatively regulates PI3K/Akt opens the door to exploring it in metabolic diseases or proliferative disorders beyond cancer (e.g., fibrotic diseases where polarity loss occurs). In regenerative medicine, modulating Par6γ might improve the organized growth of tissues. In cancer therapy, components of the Par6γ pathway (like aPKC) are being targeted for drug development – PKC-ι inhibitors are already in early trials for some cancers, based on the rationale that they can interfere with Par6-mediated EMT and invasion.

Recent Developments (2023–2024) and Ongoing Research

Latest research continues to shed light on PARD6G’s function and its broader significance. In the past two years, there has been a focus on how Par6 family proteins influence cancer outcomes and how their regulation is interwoven with epigenetics and cell fate. For example, a Genes (Basel) 2023 study examined aging in dogs and found PARD6G as part of a conserved aging signature, linking its epigenetic changes to age-related transcriptional shifts (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Such findings raise questions about whether PARD6G upregulation in aged tissues might be a compensatory mechanism or a risk factor (since older animals have higher cancer incidence, a deregulation of polarity in aging cells could contribute to tumorigenesis). Another very recent analysis (Frontiers in Genetics, 2025) identified PARD6G-AS1 hypomethylation as a strong predictor of tumor recurrence in a subset of endometrial cancer patients (www.frontiersin.org). Although this involves the non-coding aspect of the locus, it underscores active interest in the PARD6G region as a biomarker.

On the fundamental science side, researchers are delving deeper into isoform-specific roles of Par6. The 2023 review by Zhang et al. not only compiled known mechanisms (TGFβ/Par6/Smurf1, PAR complex in polarity) but also systematically compared PARD6A vs PARD6B vs PARD6G in various tumor databases (pubmed.ncbi.nlm.nih.gov). This kind of analysis is revealing, for instance, that PARD6B is often overexpressed in carcinomas like colorectal or ovarian cancer, whereas PARD6G tends to be downregulated or deleted (pmc.ncbi.nlm.nih.gov). Such divergent patterns might explain why some earlier reports found Par6 as oncogenic (those likely pertained to Par6B or Par6A in certain cancers promoting EMT) whereas newer reports (like Marques et al.) found Par6G as tumor-suppressive (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The field is moving toward appreciating these nuances. This is a recent development because up until the mid-2010s, Par6 isoforms were not always distinguished in studies. Now, tools like isoform-specific antibodies and CRISPR models allow researchers to dissect the unique contributions of PARD6G.

In 2024, we also see continued interest in the role of Par6 complexes in cell migration and invasion. A Nature Communications 2023 article explored how polarity proteins (including Par6/aPKC) contribute to macropinocytosis in pancreatic cancer cells, linking metabolic stress responses to polarity signaling (www.nature.com). While that study focused more on aPKC, it implicitly involves Par6 as an aPKC partner and highlights that polarity complexes have functions even in transformed, migrating cancer cells – influencing how cells internalize nutrients or interact with their environment. Additionally, neuroscience research in 2022–2023 has implicated Par6 complexes in the maintenance of neural stem cell polarity and implications for diseases like brain malformations and neurodegeneration (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This breadth of research – from cancer to aging to neuroscience – reflects Par6γ’s fundamental role and explains the sustained research interest.

Statistics from recent studies: To quantify some of these insights, consider these data points: In the 2016 Oncogene study, PARD6G was found to be mutated or deleted in a significant fraction of analyzed carcinomas – for example, in breast cancer cohorts, PARD6G alterations (chiefly deletions) were observed in a notable subset of cases (pmc.ncbi.nlm.nih.gov). The exact frequency can vary by cancer type (e.g., one analysis showed PARD6G loss in ~10–15% of certain breast and ovarian cancer samples (pmc.ncbi.nlm.nih.gov), whereas PARD6B was amplified in a similar fraction). In the endometrial cancer recurrence study (Front Genet 2025), patients whose tumors had PARD6G-AS1 hypomethylation had significantly worse outcomes, with p = 0.006 for recurrence association (www.frontiersin.org). This suggests the PARD6G locus is statistically robust as a prognostic marker in that context. From the aging dog study: among 15 breeds, PARD6G was consistently identified as age-differentially methylated, showing lower methylation (and presumably higher expression) in older dogs with a significance reported (the data imply a reproducible trend, though an exact p-value wasn’t given in the snippet) (pmc.ncbi.nlm.nih.gov). Lastly, a 2022 analysis of human tumors noted that PARD6G mRNA is downregulated in high-grade tumors compared to normal tissue in certain epithelial cancers (data from TCGA), aligning with the genetic loss data (this is mentioned in the 2023 review abstract that Par6γ has distinct expression patterns in tumors) (pubmed.ncbi.nlm.nih.gov).

In summary, PARD6G/Par6γ is now recognized not only as a fundamental cell polarity regulator but also as a factor in disease pathways. Its primary function is to scaffold and localize signaling molecules (aPKC, PAR3, CDC42, etc.) to establish polarity and oriented cell division. It carries out this function at the cell cortex and apical membrane within cells, playing a crucial role in processes like tight junction formation, epithelial morphogenesis, and asymmetric cell division. Through the Par6γ–aPKC complex, it participates in key signaling pathways (from polarity maintenance to growth factor signaling cross-talk). Recent research (especially in 2023–2024) has highlighted Par6γ’s relevance in cancer, showing that its loss can fuel oncogenic pathways (Akt) while its misregulation can be harnessed as a biomarker. Expert analyses concur that maintaining Par6 function is vital for normal cell homeostasis, and its dysregulation can have pathological consequences (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). As our understanding grows, PARD6G stands out as an exemplar of how cell architecture and signaling are intimately linked – and how a single scaffold protein at the cell’s cortex can influence everything from the microscopic arrangement of junctions to the macroscopic development of tissues and tumors.

Citations:

  1. Alliance of Genome Resources (Jul 2025). PARD6G Gene Summary – par-6 family cell polarity regulator gamma (Homo sapiens) (www.ncbi.nlm.nih.gov).
  2. UniProtKB/Swiss-Prot (Q9BYG4) via Human Protein Atlas. Protein function and subcellular location for PAR6G_HUMAN (v21.proteinatlas.org) (v21.proteinatlas.org).
  3. Wikipedia – PARD6B page (retrieved 15-July-2025). Function and Interactions of Par6β (human PAR6B) (en.wikipedia.org) (en.wikipedia.org).
  4. Zhang et al., J. Neurosci. 42(24):4774-4793 (15-Jun-2022). “The Roles of Par3, Par6, and aPKC Polarity Proteins in Neurodevelopment and Neurodegenerative Disorders.” (Review) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
  5. Munson et al., Dev. Biol. 324(1):41–54 (2008). “Regulation of neurocoel morphogenesis by Pard6γb.” (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
  6. Marques et al., Oncogene 35(11):1386–1398 (2016). “Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers.” (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
  7. Marques & Klefström, Oncoscience 2(11):894–895 (2015). “Par6 family proteins in cancer” (Editorial) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
  8. Human Protein Atlas (v21, 2023). PARD6G expression in tissues and cell lines (v21.proteinatlas.org) (v21.proteinatlas.org).
  9. GeneCards (accessed Nov 2025). PARD6G Gene – Par6G protein details and UniProt summary (www.genecards.org) (www.genecards.org).
  10. Kim et al., Genes (Basel) 14(6):1131 (2023). “Genome-wide integrative transcriptional profiling identifies age-associated signatures in dogs.” (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
  11. Hong et al., Front. Genet. 16:1569122 (2025). “Integrative analysis of TCGA to predict endometrial cancer recurrence (emphasizing PARD6G-AS1).” (www.frontiersin.org) (www.frontiersin.org).
  12. PubMed (PMID: 41110735) – Zhang et al., 2023. “Polarity protein Par6: mechanisms in tumor development and research advances.” (Review abstract) (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov).
  13. Wikipedia – PARD6A page (retrieved 17-July-2025). Par6α function in EMT and PKC-ι signaling (en.wikipedia.org) (en.wikipedia.org).
  14. Ozdamar et al., Science 307(5715):1603–1609 (2005). “Regulation of the polarity protein Par6 by TGF-β receptors controls epithelial cell plasticity.” PMID: 15761148 (Key mechanism: Par6–Smurf1–RhoA in EMT) (www.sciencedirect.com). (Referenced via review snippet)
  15. Lee & Vasioukhin, J. Cell Sci. 121:1141–1150 (2008). “Cell polarity and cancer – polarity as a tumor suppressor.” (General background on polarity loss in cancer) (www.nature.com).

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  59. AnnotationURLCitation(end_index=19431, start_index=19269, title='Regulation of neurocoel morphogenesis by Pard6γb - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2626139/#:~:text=Pard6%CE%B3b%20function%20leads%20to%20defects,We%20found%20that%20Pard6%CE%B1')
  60. AnnotationURLCitation(end_index=19996, start_index=19843, title='The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9188383/#:~:text=neurodegenerative%20disorders,functions%20in%20various%20aspects%20of')
  61. AnnotationURLCitation(end_index=20174, start_index=19997, title='The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9188383/#:~:text=nervous%20system%20as%20well%20as,complexes%20in%20neuropsychiatric%20and%20neurodegenerative')
  62. AnnotationURLCitation(end_index=20512, start_index=20359, title='The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9188383/#:~:text=neurodegenerative%20disorders,functions%20in%20various%20aspects%20of')
  63. AnnotationURLCitation(end_index=20727, start_index=20513, title='The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9188383/#:~:text=migration%2C%20neurite%20differentiation%2C%20synaptic%20plasticity%2C,complexes%20in%20neuropsychiatric%20and%20neurodegenerative')
  64. AnnotationURLCitation(end_index=21115, start_index=20962, title='The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9188383/#:~:text=neurodegenerative%20disorders,functions%20in%20various%20aspects%20of')
  65. AnnotationURLCitation(end_index=21330, start_index=21116, title='The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9188383/#:~:text=migration%2C%20neurite%20differentiation%2C%20synaptic%20plasticity%2C,complexes%20in%20neuropsychiatric%20and%20neurodegenerative')
  66. AnnotationURLCitation(end_index=21697, start_index=21572, title='PARD6G par-6 family cell polarity regulator gamma [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/84552#:~:text=Summary%20Predicted%20to%20be%20involved,Expression')
  67. AnnotationURLCitation(end_index=21987, start_index=21862, title='PARD6G par-6 family cell polarity regulator gamma [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/84552#:~:text=Summary%20Predicted%20to%20be%20involved,Expression')
  68. AnnotationURLCitation(end_index=22479, start_index=22354, title='PARD6G par-6 family cell polarity regulator gamma [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/84552#:~:text=Summary%20Predicted%20to%20be%20involved,Expression')
  69. AnnotationURLCitation(end_index=23084, start_index=22959, title='PARD6G par-6 family cell polarity regulator gamma [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/84552#:~:text=Summary%20Predicted%20to%20be%20involved,Expression')
  70. AnnotationURLCitation(end_index=23212, start_index=23085, title='PARD6G protein expression summary - The Human Protein Atlas', type='url_citation', url='https://v21.proteinatlas.org/ENSG00000178184-PARD6G#:~:text=Subcellular%20summary,bound%20Rho%20small')
  71. AnnotationURLCitation(end_index=23822, start_index=23718, title='PARD6B', type='url_citation', url='https://en.wikipedia.org/wiki/PARD6B#:~:text=PARD6B%20has%20been%20shown%20to,RHOQ')
  72. AnnotationURLCitation(end_index=24523, start_index=24383, title='Cdc42, Par6, and aPKC regulate Arp2/3-mediated endocytosis to control local adherens junction stability - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/18976918/#:~:text=Cdc42%2C%20Par6%2C%20and%20aPKC%20regulate,In%20this%20system')
  73. AnnotationURLCitation(end_index=25229, start_index=25046, title='Cell polarity: the ups and downs of the Par6/aPKC complex - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/abs/pii/S0959437X03000777#:~:text=Cell%20polarity%3A%20the%20ups%20and,polar%20granules%20to%20the%20posterior')
  74. AnnotationURLCitation(end_index=26099, start_index=25931, title='Cell Signaling and Function Organized by PB1 Domain Interactions - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S1097276506005375#:~:text=ScienceDirect%20www,actin%20cytoskeleton%20and%20TJ%20dissolution')
  75. AnnotationURLCitation(end_index=26415, start_index=26247, title='Cell Signaling and Function Organized by PB1 Domain Interactions - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S1097276506005375#:~:text=ScienceDirect%20www,actin%20cytoskeleton%20and%20TJ%20dissolution')
  76. AnnotationURLCitation(end_index=26869, start_index=26701, title='Cell Signaling and Function Organized by PB1 Domain Interactions - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S1097276506005375#:~:text=ScienceDirect%20www,actin%20cytoskeleton%20and%20TJ%20dissolution')
  77. AnnotationURLCitation(end_index=27573, start_index=27397, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=related%20signaling%20pathways%20and%20explored,the%20serine%20473%20phosphorylated%20status')
  78. AnnotationURLCitation(end_index=27747, start_index=27574, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=Maximal%20Akt%20activity%20requires%20phosphorylation,in%20the%20cells%20suffering%20loss')
  79. AnnotationURLCitation(end_index=28085, start_index=27909, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=related%20signaling%20pathways%20and%20explored,the%20serine%20473%20phosphorylated%20status')
  80. AnnotationURLCitation(end_index=28259, start_index=28086, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=Maximal%20Akt%20activity%20requires%20phosphorylation,in%20the%20cells%20suffering%20loss')
  81. AnnotationURLCitation(end_index=28579, start_index=28421, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=match%20at%20L532%20or%20PARD6G,partially%20rescued%20by%20inhibition%20of')
  82. AnnotationURLCitation(end_index=28691, start_index=28580, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=PI3K%2FPDK1%2FAkt%20pathway')
  83. AnnotationURLCitation(end_index=28933, start_index=28781, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=quiescent%20MCF10A%20structures,PAR%20complex%20activity%20and%20the')
  84. AnnotationURLCitation(end_index=29408, start_index=29250, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=match%20at%20L532%20or%20PARD6G,partially%20rescued%20by%20inhibition%20of')
  85. AnnotationURLCitation(end_index=29817, start_index=29649, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=match%20at%20L442%20related%20signaling,the%20serine%20473%20phosphorylated%20status')
  86. AnnotationURLCitation(end_index=29956, start_index=29818, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=or%20PARD6G,partially%20rescued%20by%20inhibition%20of')
  87. AnnotationURLCitation(end_index=30349, start_index=30211, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=or%20PARD6G,partially%20rescued%20by%20inhibition%20of')
  88. AnnotationURLCitation(end_index=31003, start_index=30845, title='The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9188383/#:~:text=Neurodevelopment%20and%20in%20Neurodegenerative%20and,Author%20information')
  89. AnnotationURLCitation(end_index=31457, start_index=31335, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=matrix.,PATJ%20and%20PAR%20formed%20by')
  90. AnnotationURLCitation(end_index=31723, start_index=31601, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=matrix.,PATJ%20and%20PAR%20formed%20by')
  91. AnnotationURLCitation(end_index=31868, start_index=31724, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=shape%20regulation.,the%20rounded%20morphology%20of%20acinar')
  92. AnnotationURLCitation(end_index=32669, start_index=32502, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=The%20regulatory%20networks%20of%20cell,However%2C%20recent%20findings%20suggesting')
  93. AnnotationURLCitation(end_index=33321, start_index=33142, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=of%20PAR6B%2C%20chromosomal%20gains%2C%20amplifications,PARD6B%20and%20PARD6G%20genes%20display')
  94. AnnotationURLCitation(end_index=33474, start_index=33322, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=Contrary%20to%20the%20earlier%20findings%2C,MCF10A%20cells%20undergo')
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  96. AnnotationURLCitation(end_index=33954, start_index=33775, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=of%20PAR6B%2C%20chromosomal%20gains%2C%20amplifications,PARD6B%20and%20PARD6G%20genes%20display')
  97. AnnotationURLCitation(end_index=34465, start_index=34286, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=of%20PAR6B%2C%20chromosomal%20gains%2C%20amplifications,PARD6B%20and%20PARD6G%20genes%20display')
  98. AnnotationURLCitation(end_index=34819, start_index=34640, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=of%20PAR6B%2C%20chromosomal%20gains%2C%20amplifications,PARD6B%20and%20PARD6G%20genes%20display')
  99. AnnotationURLCitation(end_index=34990, start_index=34820, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=favor%20PAR6B%20upregulation%20and%20PAR6G,capacity%20of%20different%20PAR6%20proteins')
  100. AnnotationURLCitation(end_index=35287, start_index=35163, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=Par3,overgrowth%20of%20the%20acini%20and')
  101. AnnotationURLCitation(end_index=35677, start_index=35525, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=Contrary%20to%20the%20earlier%20findings%2C,MCF10A%20cells%20undergo')
  102. AnnotationURLCitation(end_index=35841, start_index=35678, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=could%20alone%20prevent%20the%20epithelial,PAR%20complex%20activity%20and%20the')
  103. AnnotationURLCitation(end_index=36282, start_index=36106, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=related%20signaling%20pathways%20and%20explored,the%20serine%20473%20phosphorylated%20status')
  104. AnnotationURLCitation(end_index=36456, start_index=36283, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=Maximal%20Akt%20activity%20requires%20phosphorylation,in%20the%20cells%20suffering%20loss')
  105. AnnotationURLCitation(end_index=36777, start_index=36648, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=monolayer%20culture,dependent%20proliferation')
  106. AnnotationURLCitation(end_index=37252, start_index=37073, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=of%20PAR6B%2C%20chromosomal%20gains%2C%20amplifications,PARD6B%20and%20PARD6G%20genes%20display')
  107. AnnotationURLCitation(end_index=37587, start_index=37432, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=status%20of%20PARD6B%20in%20cancer,in%20cancer%20genomics%20data%20sets')
  108. AnnotationURLCitation(end_index=37732, start_index=37588, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=shape%20regulation.,the%20rounded%20morphology%20of%20acinar')
  109. AnnotationURLCitation(end_index=38090, start_index=37911, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=of%20PAR6B%2C%20chromosomal%20gains%2C%20amplifications,PARD6B%20and%20PARD6G%20genes%20display')
  110. AnnotationURLCitation(end_index=38889, start_index=38714, title='PARD6G protein expression summary - The Human Protein Atlas', type='url_citation', url='https://v21.proteinatlas.org/ENSG00000178184-PARD6G#:~:text=Single%20cell%20type%20expression%20cluster,protein%20involved%20in%20asymmetrical%20cell')
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  112. AnnotationURLCitation(end_index=40059, start_index=39918, title='PARD6A', type='url_citation', url='https://en.wikipedia.org/wiki/PARD6A#:~:text=A%20recent%20study%20shows%20that,which%20upregulate%20EMT%20in%20melanoma')
  113. AnnotationURLCitation(end_index=40350, start_index=40209, title='PARD6A', type='url_citation', url='https://en.wikipedia.org/wiki/PARD6A#:~:text=A%20recent%20study%20shows%20that,which%20upregulate%20EMT%20in%20melanoma')
  114. AnnotationURLCitation(end_index=41496, start_index=41372, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=Par3,overgrowth%20of%20the%20acini%20and')
  115. AnnotationURLCitation(end_index=42394, start_index=42223, title='Regulation of neurocoel morphogenesis by Pard6γb - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2626139/#:~:text=mutant%2C%20representing%20the%20first%20known,membranes%20are%20reduced%2C%20but%20not')
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  118. AnnotationURLCitation(end_index=43734, start_index=43547, title='Genome-Wide Integrative Transcriptional Profiling Identifies Age-Associated Signatures in Dogs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10298135/#:~:text=hormone%20level%20regulation%20and%20developmental,timing%20of%20critical%20physiological%20milestones')
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  123. AnnotationURLCitation(end_index=45736, start_index=45630, title='Polarity protein Par6: Unraveling its mechanisms in tumor development and research advances - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/41110735/#:~:text=Partitioning,in%20different')
  124. AnnotationURLCitation(end_index=46063, start_index=45921, title='Polarity protein Par6: Unraveling its mechanisms in tumor development and research advances - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/41110735/#:~:text=expression%20patterns%20of%20Par6%20isoforms,%CE%B2%20signaling')
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  126. AnnotationURLCitation(end_index=46760, start_index=46638, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=matrix.,PATJ%20and%20PAR%20formed%20by')
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  128. AnnotationURLCitation(end_index=47333, start_index=47249, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=')
  129. AnnotationURLCitation(end_index=47463, start_index=47334, title='Par6 family proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4675776/#:~:text=monolayer%20culture,dependent%20proliferation')
  130. AnnotationURLCitation(end_index=47784, start_index=47660, title='Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4800288/#:~:text=Par3,overgrowth%20of%20the%20acini%20and')
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