LIMK1/TPPP1/HDAC6 Is a Dual Actin and Microtubule Regulatory Complex That Promotes Drug Resistance

Abstract

In this study , we identified a novel protein complex consisting of LIM-Kinase 1 (LIMK1), Histone deacetylase 6 (HDAC6) and Tubulin Polymerization Promoting Protein 1 (TPPP1). Under basal conditions, assembly of the LIMK1/TPPP1/HDAC6 complex results in both inhibition of HDAC6 activity and LIMK1 activation. This leads to increased microtubule (MT) acetylation, a MT stabilizing modification, and actin filament (F-actin) destabilization. In response to activation of the Rhokinase (ROCK) signaling pathway, downstream phosphorylation of LIMK1 and TPPP1 leads to the dissociation of the LIMK1/TPPP1/HDAC6 complex. In turn, HDAC6 and LIMK1 activities are increased, which results in MT destabilization and F-actin stabilization. Finally, we reveal that increasing tubulin acetylation reduces the efficacy of chemotherapeutic drugs, suggesting that strategies to reduce acetyl-tubulin levels may be a viable option in treating drug-resistant tumors.