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J. Biol. Chem., Vol. 280, Issue 39, 33101-33108, September 30, 2005

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Calmodulin-dependent Protein Kinase IV Regulates Hematopoietic Stem Cell Maintenance^*

Christine M. Kitsos1, Uma Sankar1, Maddalena Illario¶, Josep M. Colomer-Font, Andrew W. Duncan, Thomas J. Ribar, Tannishtha Reya, and Anthony R. Means2

From the Department of Pharmacology and Cancer Biology, Duke University, Medical Center, Durham, North Carolina 27715, the ^¶Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita Federico II, Naples 80131, Italy, and the Transform Pharmaceuticals, Emerging Sciences and Technology Division, Lexington, Massachusetts 02421

The hematopoietic stem cell (HSC) gives rise to all mature, terminally differentiated cells of the blood. Here we show that calmodulin-dependent protein kinase IV (CaMKIV) is present in c-Kit⁺ ScaI⁺ Lin^–/low hematopoietic progenitor cells (KLS cells) and that its absence results in hematopoietic failure, characterized by a diminished KLS cell population and by an inability of these cells to reconstitute blood cells upon serial transplantation. KLS cell failure in the absence of CaMKIV is correlated with increased apoptosis and proliferation of these cells in vivo and in vitro. In turn, these cell biological defects are correlated with decreases in CREB-serine 133 phosphorylation as well as in CREB-binding protein (CBP) and Bcl-2 levels. Re-expression of CaMKIV in Camk4^––KLS cells results in the rescue of the proliferation defects in vitro as well as in the restoration of CBP and Bcl-2 to wild type levels. These studies show that CaMKIV is a regulator of HSC homeostasis and suggest that its effects may be in part mediated via regulation of CBP and Bcl-2.

Received for publication, May 11, 2005 , and in revised form, June 24, 2005.

^* This work was supported by a fellowship from the SASS Medical Research Foundation(to C. M. K.) and by an National Institutes of Health grant (to A. R. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

This article was selected as a Paper of the Week.

¹ These authors contributed equally to the work.

² To whom correspondence should be addressed. Tel.: 919-681-6209; Fax: 919-681-7767;E-mail: means001{at}mc.duke.edu.

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