Developmental Cell
Volume 26, Issue 3, 12 August 2013, Pages 292-302
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Article
The Cell Polarity Protein mInsc Regulates Neutrophil Chemotaxis via a Noncanonical G Protein Signaling Pathway

https://doi.org/10.1016/j.devcel.2013.06.008Get rights and content
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Highlights

  • mInsc regulates directional movement during neutrophil chemotaxis

  • Chemoattractants induced Gαi-GDP accumulation at the front of migrating neutrophils

  • Gαi-GDP interacts with mInsc via LGN/AGS3 to recruit the Par-aPKC complex

  • Both mInsc and aPKC are required for directional control, but not for cell motility

Summary

Successful chemotaxis requires not only increased motility but also sustained directionality. Here, we show that, during neutrophil chemotaxis via receptors coupled with the Gi family of heterotrimeric G proteins, directional movement is regulated by mInsc, a mammalian protein distantly related to the Drosophila polarity-organizer Inscuteable. The GDP-bound, Gβγ-free Gαi subunit accumulates at the front of chemotaxing neutrophils to recruit mInsc—complexed with the Par3-aPKC evolutionarily conserved polarity complex—via LGN/AGS3 that simultaneously binds to Gαi-GDP and mInsc. Both mInsc-deficient and aPKC-blocked neutrophils exhibit a normal motile activity but migrate in an undirected manner. mInsc deficiency prevents neutrophils from efficiently stabilizing pseudopods at the leading edge; the stability is restored by wild-type mInsc, but not by a mutant protein defective in binding to LGN/AGS3. Thus, mInsc controls directional migration via noncanonical G protein signaling, in which Gβγ-free Gαi-GDP, a product from Gαi-GTP released after receptor activation, plays a central role.

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