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Vol. 15, Issue 3, 1224-1232, March 2004

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Phosphorylation of High-Mobility Group Protein A2 by Nek2 Kinase during the First Meiotic Division in Mouse Spermatocytes

Silvia Di Agostino ^*, Monica Fedele , Paolo Chieffi , Alfredo Fusco , Pellegrino Rossi ^*, Raffaele Geremia ^*, and Claudio Sette ^* 

^* Dipartimento di Sanità Pubblica e Biologia Cellulare, University of Rome "Tor Vergata," 00133 Rome, Italy; Istituto di Endocrinologia e Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, University of Naples "Federico II," 80131 Naples, Italy; and Dipartimento di Medicina Sperimentale, II University of Naples, 80138 Naples, Italy

Submitted September 3, 2003; Revised November 12, 2003; Accepted November 18, 2003
Monitoring Editor: Joseph Gall

The mitogen-activated protein kinase (MAPK) pathway is required for maintaining the chromatin condensed during the two meiotic divisions and to avoid a second round of DNA duplication. However, molecular targets of the MAPK pathway on chromatin have not yet been identified. Here, we show that the architectural chromatin protein HMGA2 is highly expressed in male meiotic cells. Furthermore, Nek2, a serine-threonine kinase activated by the MAPK pathway in mouse pachytene spermatocytes, directly interacts with HMGA2 in vitro and in mouse spermatocytes. The interaction does not depend on the activity of Nek2 and seems constitutive. On progression from pachytene to metaphase, Nek2 is activated and HMGA2 is phosphorylated in an MAPK-dependent manner. We also show that Nek2 phosphorylates in vitro HMGA2 and that this phosphorylation decreases the affinity of HMGA2 for DNA and might favor its release from the chromatin. Indeed, we find that most HMGA2 associates with chromatin in mouse pachytene spermatocytes, whereas it is excluded from the chromatin upon the G2/M progression. Because hmga2-/- mice are sterile and show a dramatic impairment of spermatogenesis, it is possible that the functional interaction between HMGA2 and Nek2 plays a crucial role in the correct process of chromatin condensation in meiosis.

Corresponding author. E-mail address: claudio.sette{at}uniroma2.it.

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