Mechanism of activation of an ancestral Tec kinase by PIP ₃

The TEC kinases are a family of five paralogous mammalian genes that play crucial roles in cell growth, proliferation and differentiation, particularly in immune cells. The recruitment and activation of the TEC kinases depend on the generation of the lipid second messenger, PIP ₃ , in the plasma membrane. However, the mechanisms by which PIP ₃ activates the TEC kinases are not well understood. We have elucidated the autoinhibited conformation of an ancestral TEC kinase from the choanoflagellate Monosiga brevicollis. We demonstrate that PIP ₃ relieves autoinhibition of MbTEC by displacing its PH domain from an evolutionarily conserved inhibitory interaction with its kinase domain. We also show that a conserved polyproline motif within MbTEC promotes its activation in a kinase-intrinsic mechanism. Finally, we show that the PH domain is sufficient to restore autoinhibition in a constitutively active mutant of MbTEC. Our findings reveal that PIP ₃ is necessary and sufficient for both MbTEC activation and inactivation.