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The p38/MAPK pathway regulates microtubule polymerization through phosphorylation of MAP4 and Op18 in hypoxic cells

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Abstract

In both cardiomyocytes and HeLa cells, hypoxia (1% O2) quickly leads to microtubule disruption, but little is known about how microtubule dynamics change during the early stages of hypoxia. We demonstrate that microtubule associated protein 4 (MAP4) phosphorylation increases while oncoprotein 18/stathmin (Op18) phosphorylation decreases after hypoxia, but their protein levels do not change. p38/MAPK activity increases quickly after hypoxia concomitant with MAP4 phosphorylation, and the activated p38/MAPK signaling leads to MAP4 phosphorylation and to Op18 dephosphorylation, both of which induce microtubule disruption. We confirmed the interaction between phospho-p38 and MAP4 using immunoprecipitation and found that SB203580, a p38/MAPK inhibitor, increases and MKK6(Glu) overexpression decreases hypoxic cell viability. Our results demonstrate that hypoxia induces microtubule depolymerization and decreased cell viability via the activation of the p38/MAPK signaling pathway and changes the phosphorylation levels of its downstream effectors, MAP4 and Op18.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 309015638), the Key Project of China National Programs for Basic Research and Development (973 program, 2005CB522601), and the Program for Changjiang Scholars and Innovative Research Team in University (IRT0712). The authors thank Dr. T. FitzGibbon for comments and suggestions of earlier versions of the paper.

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Authors and Affiliations

  1. State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, 400038, Chongqing, People’s Republic of China

    Jiong-Yu Hu, Zhi-Gang Chu, Yong-ming Dang, Hong Yan, Qiong Zhang, Guang-ping Liang & Yue-Sheng Huang

  2. Department of Gynecology and Obstetrics, Daping Hospital, The Third Military Medical University, 400038, Chongqing, People’s Republic of China

    Jian Han

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  1. Jiong-Yu Hu
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Correspondence to Yue-Sheng Huang.

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J.-Y. Hu and Z.-G. Chu contributed equally to this work.

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Hu, JY., Chu, ZG., Han, J. et al. The p38/MAPK pathway regulates microtubule polymerization through phosphorylation of MAP4 and Op18 in hypoxic cells. Cell. Mol. Life Sci. 67, 321–333 (2010). https://doi.org/10.1007/s00018-009-0187-z

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