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.
Highlights
The LIM-kinase (LIMK) family of proteins kinases including LIM-Kinase 1 (LIMK1) and LIMK2, promote actin polymerization by phosphorylation and inhibition of the actin depolymerizing and severing proteins cofilin/ADF [1] [2]
Previous studies reported that the LIM-kinase (LIMK) family members LIMK1 and LIMK2 interact with the microtubule regulatory protein Tubulin Polymerization Promoting Protein 1 (TPPP1) [6] [8] [17]
These results demonstrate that the LIMK1/TPPP1/Histone deacetylase 6 (HDAC6) trimer has a dual role of inhibiting HDAC6 activity and preventing LIMK1 activation to increase MT acetylation and stability as well as increasing cofilin activity and actin depolymerization
Summary
The LIM-kinase (LIMK) family of proteins kinases including LIMK1 and LIMK2, promote actin polymerization by phosphorylation and inhibition of the actin depolymerizing and severing proteins cofilin/ADF [1] [2]. (2014) LIMK1/TPPP1/HDAC6 Is a Dual Actin and Microtubule Regulatory Complex That Promotes Drug Resistance. It has been reported that LIMK1 and LIMK2 interact with Tubulin Polymerization Promoting Protein 1 (TPPP1) in vitro and in vivo [6]-[8], TPPP1 is not a LIMK substrate in cells [9]. TPPP1 is a small protein that regulates microtubule (MT) dynamics, through two different mechanisms to promote MT polymerization; first by increasing MT polymerization kinetics and second by inhibiting the activity of Histone deacetylase 6 (HDAC6), resulting in increased MT acetylation and stabilization [10] [11]. We have recently reported that similar to the LIMKs, TPPP1 is a substrate of ROCK and that ROCK-mediated TPPP1 phosphorylation inhibits its ability to bind and inhibit HDAC6 activity [9]
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