TITLE:
LIMK1/TPPP1/HDAC6 Is a Dual Actin and Microtubule Regulatory Complex That Promotes Drug Resistance
AUTHORS:
Alice V. Schofield, Cristina Gamell, Ora Bernard
KEYWORDS:
Actin; Deacetylase; Drug Sensitivity; Kinase; Microtubules
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.5 No.4,
March
12,
2014
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.