Atypical Protein Kinase C Promotes its own Asymmetric Localisation by Phosphorylating Cdc42 in Polarising Cells

Packer, J.; Gubieda, A. G.; Brooks, A.; Deutz, L. N.; Squires, I.; Ellison, S.; Naganathan, S. R.; Wollman, A. J. M.; Dickinson, D. J.; Rodriguez, J.

doi:10.1101/2023.10.27.563985

bioRxiv · 10.1101/2023.10.27.563985

Atypical Protein Kinase C Promotes its own Asymmetric Localisation by Phosphorylating Cdc42 in Polarising Cells

Packer, J.·Gubieda, A. G.·Brooks, A.·Deutz, L. N.·Squires, I.·Ellison, S.·Naganathan, S. R.·Wollman, A. J. M.·Dickinson, D. J.·Rodriguez, J.

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Abstract

Atypical protein kinase C (aPKC) is a major regulator of cell polarity. Acting in conjunction with Par6, Par3 and the small GTPase Cdc42, aPKC becomes asymmetrically localised and drives the polarisation of cells. aPKC activity is crucial for its own asymmetric localisation, suggesting a hitherto unknown feedback mechanism contributing to polarisation. Here we show in the C. elegans zygote that the feedback relies on aPKC phosphorylation of Cdc42 at serine 71. The turnover of CDC-42 phosphorylation ensures optimal aPKC asymmetry and activity throughout polarisation by tuning Par6/aPKC association with Par3 and Cdc42. Moreover, turnover of Cdc42 phosphorylation regulates actomyosin cortex dynamics that are known to drive aPKC asymmetry. Given the widespread role of aPKC and Cdc42 in cell polarity, this form of self-regulation of aPKC may be vital for the robust control of polarisation in many cell types. Key findings/graphical abstract- Phosphorylation of CDC-42 by aPKC accelerates aPKC dissociation from CDC-42, limiting aPKC activity - CDC-42/aPKC dissociation promotes aPKC association with PAR-3 and, thereby, aPKC asymmetry due to actomyosin flow - Cycling of CDC-42 phosphorylation fuels the exchange of aPKC between anteriorly transported PAR-3 and aPKC-active CDC-42 complexes - Turnover of CDC-42 phosphorylation alternates its association with effectors, aPKC and MRCK-1, ensuring proper actomyosin dynamics O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/563985v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@e0ec65org.highwire.dtl.DTLVardef@c00b8dorg.highwire.dtl.DTLVardef@36565dorg.highwire.dtl.DTLVardef@160149a_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Packer, J., Gubieda, A. G., Brooks, A., Deutz, L. N., Squires, I., Ellison, S., Naganathan, S. R., Wollman, A. J. M., Dickinson, D. J., Rodriguez, J.. 2023-10-28. Atypical Protein Kinase C Promotes its own Asymmetric Localisation by Phosphorylating Cdc42 in Polarising Cells. https://doi.org/10.1101/2023.10.27.563985

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