Control of integrin activity is vital during development and tissue homeostasis, while derailment of integrin function contributes to pathophysiological processes. Phosphorylation of a conserved threonine motif (T788/T789) in the integrin β cytoplasmic domain increases integrin activity. Here, we report that T788/T789 functions as a phospho-switch, which determines the association with either talin and kindlin-2, the major integrin activators, or filaminA, an integrin activity suppressor. A genetic screen identifies the phosphatase PPM1F as the critical enzyme, which selectively and directly dephosphorylates the T788/T789 motif. PPM1F-deficient cell lines show constitutive integrin phosphorylation, exaggerated talin binding, increased integrin activity, and enhanced cell adhesion. These gain-of-function phenotypes are reverted by reexpression of active PPM1F, but not a phosphatase-dead mutant. Disruption of the ppm1f gene in mice results in early embryonic death at day E10.5. Together, PPM1F controls the T788/T789 phospho-switch in the integrin β1 cytoplasmic tail and constitutes a novel target to modulate integrin activity.
PPM1F controls integrin activity via a conserved phospho-switch
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Tanja M. Grimm, Nina I. Dierdorf, Karin Betz, Christoph Paone, Christof R. Hauck; PPM1F controls integrin activity via a conserved phospho-switch. J Cell Biol 7 December 2020; 219 (12): e202001057. doi: https://doi.org/10.1083/jcb.202001057
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