Phosphoinositide specificity determines which cytohesins regulate beta 1 integrin recycling

Phosphoinositide specificity determines which cytohesins regulate beta 1 integrin recycling
오승자Lorraine C. Santy
Issue Date
Journal of cell science
VOL 125, NO 13-3201
Recycling of internalized integrins is a crucial step in adhesion remodeling and cell movement. Recently, we determined that the ADP-ribosylation factor-guanine nucleotide exchange factors (ARF-GEFs) cytohesin 2/ARNO and cytohesin 3/GRP1 have opposing effects on adhesion and stimulated beta 1 integrin recycling even though they are very closely related proteins (80% sequence identity). We have now determined the sequence differences underlying the differential actions of cytohesin 2/ARNO and cytohesin 3/GRP1. We found that the ability of cytohesins to promote beta 1 integrin recycling and adhesion depends upon the presence or absence of a key glycine residue in their pleckstrin homology (PH) domains. This glycine residue determines the phosphoinositide specificity and affinity of cytohesin PH domains. Switching the number of glycines in the PH domains of cytohesin 2 and cytohesin 3 is sufficient to reverse their effects on adhesion and spreading and to reverse their subcellular locations. Importantly, we also find that a mutant form of cytohesin 3/GRP1 that has three rather than two glycines in its PH domain rescues beta 1 integrin recycling in cytohesin 2/ARNO knockdown cells. Conversely, a mutant form of cytohesin 2/ARNO with two glycines in its PH domain fails to rescue b1 integrin recycling. Therefore, we conclude that phosphoinositide specificity is the sole functional difference that determines which cytohesin can promote integrin recycling.
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