DYRK1A Interacts with the Tuberous Sclerosis Complex and Promotes mTORC1 Activity

Abstract

AbstractDYRK1A, a ubiquitously expressed kinase, is linked to the dominant intellectual developmental disorder, microcephaly and Down syndrome in humans. It regulates numerous cellular processes such cell cycle, vesicle trafficking and microtubule assembly. DYRK1A is a critical regulator of organ growth, however, how it regulates organ growth is not fully understood. Here we show that knockdown ofDYRK1Aresults in reduced cell size, which is dependent on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the Tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Further, we show that DYRK1A phosphorylates TSC2 at T1462, a modification that is known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through an inhibitory phosphorylation on TSC2 and thereby promotes mTORC1 activity. Further, usingDrosophilaneuromuscular junction as model, we show that themnb, the fly homologues ofDYRK1A, is rescued by RHEB overexpression suggesting a conserved role ofDYRK1Ain TORC1 regulation.