The distinct localization of CDC42 isoforms is responsible for their specific functions during migration

Yamini Ravichandran (1, 2) , Jan Hänisch (1) , Kerren Murray (1) , Vanessa Roca (1) , Florent Dingli (3, 4) , Damarys Loew (3, 4) , Valentin Sabatet (3, 4) , Batiste Boëda (1) , Theresia E Stradal (5) , Sandrine Etienne-Manneville (1)

1 Polarité cellulaire, Migration et Cancer - Cell Polarity, Migration and Cancer
2 Collège Doctoral
3 PSL - Université Paris Sciences et Lettres
4 Laboratoire de Spectrométrie de Masse Protéomique
5 HZI - Helmholtz Centre for Infection Research

The small G-protein CDC42 is an evolutionary conserved polarity protein and a key regulator of polarized cell functions, including directed cell migration. In vertebrates, alternative splicing gives rise to two CDC42 proteins: the ubiquitously expressed isoform (CDC42u) and the brain isoform (CDC42b), which only differ in their carboxy-terminal sequence, including the CAAX motif essential for their association with membranes. We show that these divergent sequences do not directly affect the range of CDC42’s potential binding partners but indirectly influence CDC42-driven signaling by controlling the subcellular localization of the two isoforms. In astrocytes and neural precursors, which naturally express both variants, CDC42u associates with the leading-edge plasma membrane of migrating cells, where it recruits the Par6-PKCζ complex to fulfill its polarity function. In contrast, CDC42b mainly localizes to intracellular membrane compartments, where it regulates N-WASP-mediated endocytosis. Both CDC42 isoforms contribute their specific functions to promote the chemotaxis of neural precursors, demonstrating that their expression pattern is decisive for tissue-specific cell behavior.

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]

Yamini Ravichandran, Jan Hänisch, Kerren Murray, Vanessa Roca, Florent Dingli, et al.. The distinct localization of CDC42 isoforms is responsible for their specific functions during migration. Journal of Cell Biology, 2024, 223 (3), pp.e202004092. ⟨10.1083/jcb.202004092⟩. ⟨pasteur-04529566⟩