Cooperative regulation of C1-domain membrane recruitment polarizes atypical Protein Kinase C

Recruitment of the Par complex protein atypical Protein Kinase C (aPKC) to a specific membrane domain is a key step in the polarization of animal cells. While numerous proteins and phospholipids interact with aPKC, how these interactions cooperate to control its membrane recruitment has been unknown. Here we identify aPKC's C1 domain as a phospholipid interaction module that targets aPKC to the membrane of Drosophila neural stem cells (NSCs). The isolated C1 binds the NSC membrane in an unpolarized manner during interphase and mitosis and is uniquely sufficient among aPKC domains for targeting. Other domains, including the catalytic module and those that bind the upstream regulators Par-6 and Baz, restrict C1's membrane targeting activity spatially and temporally-to the apical NSC membrane during mitosis. Our results suggest that Par complex polarity results from cooperative activation of autoinhibited C1 membrane binding activity.

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Faculty Opinions recommendation of Atypical protein kinase C-zeta is essential for delayed phagocytosis of Helicobacter pylori.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1004446.161957 ◽

2002 ◽

Author(s):

David Underhill

Keyword(s):

Helicobacter Pylori ◽

Protein Kinase C ◽

Protein Kinase ◽

Atypical Protein Kinase C ◽

Atypical Protein Kinase ◽

Kinase C ◽

Protein Kinase C Zeta

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Faculty Opinions recommendation of The von Hippel-Lindau tumor suppressor protein mediates ubiquitination of activated atypical protein kinase C.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1002435.25855 ◽

2001 ◽

Author(s):

Eamonn Maher

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Tumor Suppressor ◽

Tumor Suppressor Protein ◽

Atypical Protein Kinase C ◽

Atypical Protein Kinase ◽

Von Hippel Lindau ◽

Kinase C

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Faculty Opinions recommendation of Exercise improves phosphatidylinositol-3,4,5-trisphosphate responsiveness of atypical protein kinase C and interacts with insulin signalling to peptide elongation in human skeletal muscle.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1089955.543122 ◽

2008 ◽

Author(s):

Mark Hargreaves

Keyword(s):

Skeletal Muscle ◽

Protein Kinase C ◽

Protein Kinase ◽

Human Skeletal Muscle ◽

Insulin Signalling ◽

Atypical Protein Kinase C ◽

Atypical Protein Kinase ◽

Kinase C ◽

Peptide Elongation

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Faculty Opinions recommendation of GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717988280.793472704 ◽

2013 ◽

Author(s):

David Wotton

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Basal Cell ◽

Atypical Protein Kinase C ◽

Atypical Protein Kinase ◽

Kinase C ◽

Basal Cell Carcinomas

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Faculty Opinions recommendation of Overexpression of atypical protein kinase C in HeLa cells facilitates macropinocytosis via Src activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718295550.793495175 ◽

2014 ◽

Author(s):

Vladimir Marshansky

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Hela Cells ◽

Atypical Protein Kinase C ◽

Atypical Protein Kinase ◽

Kinase C ◽

Src Activation

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Faculty Opinions recommendation of Loss of the polarity protein PAR3 activates STAT3 signaling via an atypical protein kinase C (aPKC)/NF-κB/interleukin-6 (IL-6) axis in mouse mammary cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725347358.793505708 ◽

2015 ◽

Author(s):

Andrew Goryachev

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Interleukin 6 ◽

Mammary Cells ◽

Atypical Protein Kinase C ◽

Atypical Protein Kinase ◽

Stat3 Signaling ◽

Kinase C

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Identification of Key Phospholipids That Bind and Activate Atypical PKCs

Biomedicines ◽

10.3390/biomedicines9010045 ◽

2021 ◽

Vol 9 (1) ◽

pp. 45

Author(s):

Suresh Velnati ◽

Sara Centonze ◽

Federico Girivetto ◽

Daniela Capello ◽

Ricardo M. Biondi ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Phosphatidic Acid ◽

Kinase Activity ◽

Membrane Lipids ◽

Atypical Protein Kinase C ◽

Atypical Protein Kinase ◽

Kinase C ◽

Specific Regulation ◽

Phosphatidylinositol 4

PKCζ and PKCι/λ form the atypical protein kinase C subgroup, characterised by a lack of regulation by calcium and the neutral lipid diacylglycerol. To better understand the regulation of these kinases, we systematically explored their interactions with various purified phospholipids using the lipid overlay assays, followed by kinase activity assays to evaluate the lipid effects on their enzymatic activity. We observed that both PKCζ and PKCι interact with phosphatidic acid and phosphatidylserine. Conversely, PKCι is unique in binding also to phosphatidylinositol-monophosphates (e.g., phosphatidylinositol 3-phosphate, 4-phosphate, and 5-phosphate). Moreover, we observed that phosphatidylinositol 4-phosphate specifically activates PKCι, while both isoforms are responsive to phosphatidic acid and phosphatidylserine. Overall, our results suggest that atypical Protein kinase C (PKC) localisation and activity are regulated by membrane lipids distinct from those involved in conventional PKCs and unveil a specific regulation of PKCι by phosphatidylinositol-monophosphates.

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Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling

Molecular Biology of the Cell ◽

10.1091/mbc.e15-05-0265 ◽

2015 ◽

Vol 26 (20) ◽

pp. 3578-3595 ◽

Cited By ~ 29

Author(s):

Andrew Archibald ◽

Maia Al-Masri ◽

Alyson Liew-Spilger ◽

Luke McCaffrey

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Epithelial Cells ◽

3D Culture ◽

Cell Junctions ◽

Nuclear Accumulation ◽

Cell Phenotype ◽

Atypical Protein Kinase C ◽

Atypical Protein Kinase ◽

Kinase C

Epithelial cells are major sites of malignant transformation. Atypical protein kinase C (aPKC) isoforms are overexpressed and activated in many cancer types. Using normal, highly polarized epithelial cells (MDCK and NMuMG), we report that aPKC gain of function overcomes contact inhibited growth and is sufficient for a transformed epithelial phenotype. In 2D cultures, aPKC induced cells to grow as stratified epithelia, whereas cells grew as solid spheres of nonpolarized cells in 3D culture. aPKC associated with Mst1/2, which uncoupled Mst1/2 from Lats1/2 and promoted nuclear accumulation of Yap1. Of importance, Yap1 was necessary for aPKC-mediated overgrowth but did not restore cell polarity defects, indicating that the two are separable events. In MDCK cells, Yap1 was sequestered to cell–cell junctions by Amot, and aPKC overexpression resulted in loss of Amot expression and a spindle-like cell phenotype. Reexpression of Amot was sufficient to restore an epithelial cobblestone appearance, Yap1 localization, and growth control. In contrast, the effect of aPKC on Hippo/Yap signaling and overgrowth in NMuMG cells was independent of Amot. Finally, increased expression of aPKC in human cancers strongly correlated with increased nuclear accumulation of Yap1, indicating that the effect of aPKC on transformed growth by deregulating Hippo/Yap1 signaling may be clinically relevant.

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