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01.03.21 St Johnston lab identifies RhoGAP19D as a new lateral polarity factor

last modified Mar 19, 2021 01:45 PM
Using Drosophila egg chamber follicular cells as a model system, the St Johnston lab analysed the roles of Cdc42GAPs in epithelial polarity, and identified RhoGAP19D as the one that restricts active Cdc42 to the apical domain. The absence of RhoGAP19D leads to a phenotype that mimics the early steps of carcinoma formation
01.03.21 St Johnston lab identifies RhoGAP19D as a new lateral polarity factor

Video still: stage 7 egg chamber containing a large rhogap19d mutant clone (marked by the loss of RFP; magenta) and expressing GFP-aPKC (green)

RhoGAP19D inhibits Cdc42 laterally to control epithelial cell shape and prevent invasion

Fic W et al. (2021) J Cell Biol 220: e202009116.

DOI: 10.1083/jcb.202009116. 

 

Abstract from the paper

Cdc42-GTP is required for apical domain formation in epithelial cells, where it recruits and activates the Par-6–aPKC polarity complex, but how the activity of Cdc42 itself is restricted apically is unclear.

We used sequence analysis and 3D structural modeling to determine which Drosophila GTPase-activating proteins (GAPs) are likely to interact with Cdc42 and identified RhoGAP19D as the only high-probability Cdc42GAP required for polarity in the follicular epithelium.

RhoGAP19D is recruited by α-catenin to lateral E-cadherin adhesion complexes, resulting in exclusion of active Cdc42 from the lateral domain. rhogap19d mutants therefore lead to lateral Cdc42 activity, which expands the apical domain through increased Par-6/aPKC activity and stimulates lateral contractility through the myosin light chain kinase, Genghis khan (MRCK). This causes buckling of the epithelium and invasion into the adjacent tissue, a phenotype resembling that of precancerous breast lesions.

Thus, RhoGAP19D couples lateral cadherin adhesion to the apical localization of active Cdc42, thereby suppressing epithelial invasion.

 

St Johnston Fic Fig 7

Figure 7 from the paper. A revised network of inhibitory interactions between polarity factors. (A) A diagram showing how the recruitment of RhoGAP19D to the lateral membrane by E-cadherin adhesion complexes restricts Cdc42 activity to the apical domain. This adds a new inhibitory interaction to the network of inter- actions between apical and lateral polarity factors. (B) A model of the changes in rhogap19d mutant cells that lead to the invasive phenotype.

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Read more about research in the St Johnston lab.

Watch Daniel St Johnston describe his research on YouTube.

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The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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