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The KIBRA-aPKC connection: A potential regulator of membrane trafficking and cell polarity.

Yoshihama Y, Chida K, Ohno S - Commun Integr Biol (2012)

Bottom Line: Recent studies on the biochemical and cellular properties of KIBRA reveal the role of KIBRA as a regulator of membrane trafficking.Further, KIBRA directly inhibits the activity of the cell polarity regulator, aPKC, which is required for apical protein exocytosis.Here, we discuss how this KIBRA-aPKC connection, a potential regulator of membrane trafficking and cell polarity, can contribute to the recently discovered functions of KIBRA.

View Article: PubMed Central - PubMed

ABSTRACT
The kidney and brain protein (KIBRA) is a scaffold or an adaptor-like protein with WW, C2-like and atypical protein kinase C (aPKC)-binding domains. Genetic studies in Drosophila revealed that KIBRA is an upstream regulator of the conserved Hippo pathway, which is implicated in organ size determination. In addition, genome-wide studies revealed an association between the single nucleotide polymorphism in the KIBRA gene locus and human episodic memory performance. However, the mechanism of action through which KIBRA is linked to these functions remains poorly understood. Recent studies on the biochemical and cellular properties of KIBRA reveal the role of KIBRA as a regulator of membrane trafficking. Further, KIBRA directly inhibits the activity of the cell polarity regulator, aPKC, which is required for apical protein exocytosis. Here, we discuss how this KIBRA-aPKC connection, a potential regulator of membrane trafficking and cell polarity, can contribute to the recently discovered functions of KIBRA.

No MeSH data available.


Related in: MedlinePlus

Figure 2. Models of the molecular mechanism of KIBRA in regulating membrane trafficking. (A) In epithelial cells, KIBRA suppresses the kinase activity of aPKC, resulting in suppression of the trafficking of apical-containing vesicles to the cell surface or cell-cell contact site. Association between KIBRA and the exocyst complex can influence this process. (B) In neurons, KIBRA associates with PICK1 and suppresses recycling of the AMPA receptor subunit, GluR2, to the cell surface. PKMζ enhances GluR2 surface expression via regulating the NSF-mediated release of GluR2 from PICK1. KIBRA may inhibit the kinase activity of PKMζ, leading to suppression of GluR2 recycling. (C) In endosomal trafficking of TfnR, KIBRA does not affect internalization, but affects trafficking from the endosome sorting compartment to the endosomal recycling compartment. (D) In directional migration, KIBRA can affect vesicular trafficking through interaction with the exocyst complex and aPKC.
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Figure 2: Figure 2. Models of the molecular mechanism of KIBRA in regulating membrane trafficking. (A) In epithelial cells, KIBRA suppresses the kinase activity of aPKC, resulting in suppression of the trafficking of apical-containing vesicles to the cell surface or cell-cell contact site. Association between KIBRA and the exocyst complex can influence this process. (B) In neurons, KIBRA associates with PICK1 and suppresses recycling of the AMPA receptor subunit, GluR2, to the cell surface. PKMζ enhances GluR2 surface expression via regulating the NSF-mediated release of GluR2 from PICK1. KIBRA may inhibit the kinase activity of PKMζ, leading to suppression of GluR2 recycling. (C) In endosomal trafficking of TfnR, KIBRA does not affect internalization, but affects trafficking from the endosome sorting compartment to the endosomal recycling compartment. (D) In directional migration, KIBRA can affect vesicular trafficking through interaction with the exocyst complex and aPKC.

Mentions: Recent discoveries about the cellular functions of KIBRA suggest that KIBRA plays an important role in membrane homeostasis via the regulation of vesicular transport. Analysis using the Madin-Darby canine kidney (MDCK) cells, which are cultured epithelial cells derived from the canine kidney, revealed the function of KIBRA in apical plasma membrane trafficking in epithelial cells.15 Epithelial cells maintain their apical-basolateral membrane polarity by regulating the polarized trafficking machinery, which transports different plasma membrane proteins to the apical and basolateral membrane domains.19 In the absence of cell-cell contact, large intracellular vacuoles called vacuolar apical compartments (VACs) appear,20 which are thought to be normal intermediates in the biogenesis of apical surface and often result from the fusion of apical transport vesicles under conditions of reduced delivery form the apical recycling/early endosome to the apical plasma membrane.19 Even in the absence of cell-cell contact, however, KIBRA-depleted MDCK cells did not exhibit the formation of VACs.15 Furthermore, KIBRA knockdown accelerates the exocytosis of the apical protein, p75, to the cell surface under these conditions, suggesting that KIBRA exerts an inhibitory action on vesicular trafficking from the endosome to the plasma membrane (exocytosis) (Fig. 2A).15 The knockdown of KIBRA does not have any effect on apical protein internalization induced by collagen overlay, suggesting that the endocytic pathway is not affected by KIBRA.15 The involvement of KIBRA in exocytosis, but not in endocytosis, seems to be a conserved property observed in a different biological context. In hippocampal neurons, KIBRA has been shown to be involved in the suppression of AMPA receptor trafficking to the cell surface; the knockdown of KIBRA did not affect internalization of the GluR2 subunit of AMPA receptor, but accelerated the recycling speed to the cell surface14 (Fig. 2B). In another study, Traer and colleagues16 showed that KIBRA is required for the sorting of the transferrin receptor (TfnR). Knockdown of KIBRA in HeLa cells disrupted the endosomal recycling compartment, possibly due to inhibition of the trafficking between the endosomal sorting compartment to the endosomal recycling compartment (Fig. 2C). Importantly, there were no effects on the internalization of TfnR. Although this report did not examine whether the recycling of TfnR is affected by the knockdown of KIBRA, it supports the idea that KIBRA plays important roles in endosomal trafficking in various types of cells.


The KIBRA-aPKC connection: A potential regulator of membrane trafficking and cell polarity.

Yoshihama Y, Chida K, Ohno S - Commun Integr Biol (2012)

Figure 2. Models of the molecular mechanism of KIBRA in regulating membrane trafficking. (A) In epithelial cells, KIBRA suppresses the kinase activity of aPKC, resulting in suppression of the trafficking of apical-containing vesicles to the cell surface or cell-cell contact site. Association between KIBRA and the exocyst complex can influence this process. (B) In neurons, KIBRA associates with PICK1 and suppresses recycling of the AMPA receptor subunit, GluR2, to the cell surface. PKMζ enhances GluR2 surface expression via regulating the NSF-mediated release of GluR2 from PICK1. KIBRA may inhibit the kinase activity of PKMζ, leading to suppression of GluR2 recycling. (C) In endosomal trafficking of TfnR, KIBRA does not affect internalization, but affects trafficking from the endosome sorting compartment to the endosomal recycling compartment. (D) In directional migration, KIBRA can affect vesicular trafficking through interaction with the exocyst complex and aPKC.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: Figure 2. Models of the molecular mechanism of KIBRA in regulating membrane trafficking. (A) In epithelial cells, KIBRA suppresses the kinase activity of aPKC, resulting in suppression of the trafficking of apical-containing vesicles to the cell surface or cell-cell contact site. Association between KIBRA and the exocyst complex can influence this process. (B) In neurons, KIBRA associates with PICK1 and suppresses recycling of the AMPA receptor subunit, GluR2, to the cell surface. PKMζ enhances GluR2 surface expression via regulating the NSF-mediated release of GluR2 from PICK1. KIBRA may inhibit the kinase activity of PKMζ, leading to suppression of GluR2 recycling. (C) In endosomal trafficking of TfnR, KIBRA does not affect internalization, but affects trafficking from the endosome sorting compartment to the endosomal recycling compartment. (D) In directional migration, KIBRA can affect vesicular trafficking through interaction with the exocyst complex and aPKC.
Mentions: Recent discoveries about the cellular functions of KIBRA suggest that KIBRA plays an important role in membrane homeostasis via the regulation of vesicular transport. Analysis using the Madin-Darby canine kidney (MDCK) cells, which are cultured epithelial cells derived from the canine kidney, revealed the function of KIBRA in apical plasma membrane trafficking in epithelial cells.15 Epithelial cells maintain their apical-basolateral membrane polarity by regulating the polarized trafficking machinery, which transports different plasma membrane proteins to the apical and basolateral membrane domains.19 In the absence of cell-cell contact, large intracellular vacuoles called vacuolar apical compartments (VACs) appear,20 which are thought to be normal intermediates in the biogenesis of apical surface and often result from the fusion of apical transport vesicles under conditions of reduced delivery form the apical recycling/early endosome to the apical plasma membrane.19 Even in the absence of cell-cell contact, however, KIBRA-depleted MDCK cells did not exhibit the formation of VACs.15 Furthermore, KIBRA knockdown accelerates the exocytosis of the apical protein, p75, to the cell surface under these conditions, suggesting that KIBRA exerts an inhibitory action on vesicular trafficking from the endosome to the plasma membrane (exocytosis) (Fig. 2A).15 The knockdown of KIBRA does not have any effect on apical protein internalization induced by collagen overlay, suggesting that the endocytic pathway is not affected by KIBRA.15 The involvement of KIBRA in exocytosis, but not in endocytosis, seems to be a conserved property observed in a different biological context. In hippocampal neurons, KIBRA has been shown to be involved in the suppression of AMPA receptor trafficking to the cell surface; the knockdown of KIBRA did not affect internalization of the GluR2 subunit of AMPA receptor, but accelerated the recycling speed to the cell surface14 (Fig. 2B). In another study, Traer and colleagues16 showed that KIBRA is required for the sorting of the transferrin receptor (TfnR). Knockdown of KIBRA in HeLa cells disrupted the endosomal recycling compartment, possibly due to inhibition of the trafficking between the endosomal sorting compartment to the endosomal recycling compartment (Fig. 2C). Importantly, there were no effects on the internalization of TfnR. Although this report did not examine whether the recycling of TfnR is affected by the knockdown of KIBRA, it supports the idea that KIBRA plays important roles in endosomal trafficking in various types of cells.

Bottom Line: Recent studies on the biochemical and cellular properties of KIBRA reveal the role of KIBRA as a regulator of membrane trafficking.Further, KIBRA directly inhibits the activity of the cell polarity regulator, aPKC, which is required for apical protein exocytosis.Here, we discuss how this KIBRA-aPKC connection, a potential regulator of membrane trafficking and cell polarity, can contribute to the recently discovered functions of KIBRA.

View Article: PubMed Central - PubMed

ABSTRACT
The kidney and brain protein (KIBRA) is a scaffold or an adaptor-like protein with WW, C2-like and atypical protein kinase C (aPKC)-binding domains. Genetic studies in Drosophila revealed that KIBRA is an upstream regulator of the conserved Hippo pathway, which is implicated in organ size determination. In addition, genome-wide studies revealed an association between the single nucleotide polymorphism in the KIBRA gene locus and human episodic memory performance. However, the mechanism of action through which KIBRA is linked to these functions remains poorly understood. Recent studies on the biochemical and cellular properties of KIBRA reveal the role of KIBRA as a regulator of membrane trafficking. Further, KIBRA directly inhibits the activity of the cell polarity regulator, aPKC, which is required for apical protein exocytosis. Here, we discuss how this KIBRA-aPKC connection, a potential regulator of membrane trafficking and cell polarity, can contribute to the recently discovered functions of KIBRA.

No MeSH data available.


Related in: MedlinePlus