Cyclical phosphorylation of LRAP35a and CLASP2 by GSK3β and CK1δ regulates EB1-dependent MT dynamics in cell migration

Mammalian cell cytoskeletal reorganization for efficient directional movement requires tight coordination of actomyosin and microtubule networks. In this study, we show that LRAP35a potentiates microtubule stabilization by promoting CLASP2/EB1 interaction besides its complex formation with MRCK/MYO18A for retrograde actin flow. The alternate regulation of these two networks by LRAP35a is tightly regulated by a series of phosphorylation events that dictated its specificity. Sequential phosphorylation of LRAP35a by Protein Kinase A (PKA) and Glycogen Synthase Kinase-3 beta (GSK3 beta) initiates the association of LRAP35a with CLASP2, while subsequent binding and further phosphorylation by Casein Kinase 1 delta (CK1 delta) induce their dissociation, which facilitates LRAP35a/MRCK association in driving lamellar actomyosin flow. Importantly, microtubule dynamics is directly moderated by CK1 delta activity on CLASP2 to regulate GSK3 beta phosphorylation of the SxIP motifs that blocks EB1 binding, an event countered by LRAP35a interaction and its competition for CK1 delta activity. Overall this study reveals an essential role for LRAP35a in coordinating lamellar contractility and microtubule polarization in cell migration.

Automated summary

LRAP35a plays a crucial role in cell migration by coordinating lamellar contractility and microtubule polarization for efficient directional movement. Its regulation of actomyosin and microtubule networks is tightly controlled by a series of phosphorylation events, influencing the interaction and dissociation of key proteins involved in cellular movement.