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Scientists Reveal AMPK Regulates Cell Division and Central Spindle Length by Phosphorylation of KIF4A
Update time: 2017-12-11
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AMP-activated protein kinase (AMPK) is a highly conserved energy sensor composed of a catalytic α subunit, a scaffolding β subunit, and a regulatory γ subunit. AMPK is activated by stimuli such as nutrient deprivation, hypoxia and other cellular stresses.

Activated AMPK then promotes catabolic pathways to generate adenosine triphosphate (ATP) while switching off ATP-consuming pathways thereby restoring energy homeostasis. Given its role as a central kinase in coordinating cell growth with energy status, the critical roles of AMPK in metabolic regulation have been widely studied, which also has made AMPK an attractive pharmacological target for treatment of metabolic diseases like diabetes.

However, in recent years the regulation pathways of AMPK have been expanded to areas, which are not directly viewed as metabolic processes, including cell metastasis, cell polarity and cell division.

To fully understand the unexpected roles of AMPK in the context of expanding areas, researchers at Shanghai Institute of Materia Medica(SIMM, CAS, and Wu Han university firstly performed an MS-based quantitative phosphoproteomic study to identify direct AMPK phosphorylation sites. Combined with bioinformatic analysis, the research team screened out 20 new AMPK substrate candidates, 8 of which were functionally associated with cytoskeleton and cell division.

Then, the researchers systemically investigated the roles of AMPK during cell division and found that AMPK is required for appropriate cell division progression. The result also proved that KIF4A, a candidate of AMPK substrate identified in the Mass spectrometry (MS) study, is a direct AMPK substrate both in vitro and in vivo. Based on above results, the team finally expounded how KIF4A-dependent central spindle length control is elaborately regulated by AMPK- and Aurora B-dependent phosphorylation in a competitive way. As the AMPK-KIF4A regulation also responses to glucose stress, this research firstly provides a link between KIF4A-dependent central spindle length control and cellular energy stress.

The research team was led by Profs. LI Jia and ZANG Yi at SIMM as well as GUO Lin at Wu Han university. Given the relevance of ATP consumption to KIF4A activity and the differential KIF4A ATPase conferred induced by Aurora B- and AMPK dependent phosphorylations, this novel competitive phosphoregulation may act as a buffer for KIF4A to support the functional central spindle assembly in adapting glucose stress. The finding has been published in J Mol Cell Biol.

This work was supported by the National Natural Science Foundation of China, the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Institutes for Drug Discovery and Development, Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality.

Full text:

Figure: The co-localization of eGFP-AMPKα2 and endogenous KIF4A during mitosis.

Figure: The intensity ratio of central spindle KIF4A (white arrow) over chromosomal KIF4A (yellow arrow) are plotted as a function of time (mean ± SEM, n = 7–10).

Figure: A model for AMPK activity associated central spindle length control.

(Credit: LI Qianru)



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