Adaptor Protein LRAP25 Mediates MRCK Regulation of LIMK1 in Lamellipodial F-actin Dynamics [Signal Transduction]

August 8th, 2014 by Lee, I. C. J., Leung, T., Tan, I.

Myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) has been shown to localize to the lamella of mammalian cells through its interaction with an adaptor protein Leucine Repeat Adaptor Protein 35a (LRAP35a) which links it with Myosin 18A (MYO18A) for the activation of lamellar actomyosin network essential for cell migration. Here we report the identification of another adaptor protein LRAP25 that mediates MRCK association with LIMK1. The lamellipodium-localized LRAP25-MRCK complex is essential for the regulation of local LIM Kinase 1 (LIMK1) and its downstream F-actin regulatory factor cofilin. Functionally, inhibition of either MRCK or LRAP25 resulted in marked suppression of LIMK1 activity and downregulation of cofilin phosphorylation in response to aluminium fluoride induction in B16-F1 cells, which eventually resulted in deregulation of lamellipodial F-actin and reorganization of cytoskeletal structures causing defects in cell polarization and motility. These biochemical and functional characterizations thus underline the functional relevance of LRAP25-MRCK complex in LIMK1-cofilin signaling, and the importance of LRAP adaptors as key determinants of MRCK cellular localization and downstream specificities.