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Blood, 1 February 2006, Vol. 107, No. 3, pp. 870-879. Prepublished online as a Blood First Edition Paper on October 4, 2005; DOI 10.1182/blood-2005-03-0941. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: 2005-03-0941v1 107/3/870    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Goichberg, P. Articles by Lapidot, T. Search for Related Content PubMed PubMed Citation Articles by Goichberg, P. Articles by Lapidot, T. Related Collections Hematopoiesis and Stem Cells Signal Transduction Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS cAMP-induced PKC activation increases functional CXCR4 expression on human CD34+ hematopoietic progenitors Polina Goichberg, Alexander Kalinkovich, Nataliya Borodovsky, Melania Tesio, Isabelle Petit, Arnon Nagler, Izhar Hardan, and Tsvee Lapidot From the Immunology Department, The Weizmann Institute of Science, Rehovot, Israel; and the Bone Marrow Transplantation Department, Chaim Sheba Medical Center, Tel Hashomer, Israel. Chemokines are key regulators of hematopoiesis and host defense. We report here that functional expression of the chemokine receptor CXCR4 on human immature CD34+ hematopoietic progenitors was increased as a result of sustained elevation in cellular cAMP by dbcAMP and prostaglandin E2. This effect of cAMP was specifically mediated by PKC activity. CXCR4 expression and PKC activation by cAMP were decreased after the inhibition of cAMP effector-Rap1 by Spa1 overexpression. Interference with the activation of Rac1, a downstream target of Rap1, prevented the cAMP-induced increase in PKC activity and CXCR4 levels. Functional manifestation of the effects of cAMP-elevating agents revealed an increased ability of human CD34+ cells to transmigrate the bone marrow (BM) endothelial layer and adhere to BM stroma in vitro, and it augmented the homing potential to the BM and spleens of immunodeficient mice in a Rac1- and a PKC-dependent manner. cAMP- and TNF-stimulated pathways converged in PKC-activated CXCR4 expression and MMP-2/MMP-9 secretion. cAMP treatment had a beneficial effect on CD34+ cell survival in a PKC-mediated fashion. Taken together, our data reveal major roles for cAMP-induced PKC activation in signaling governing the motility and development of CD34+ cells. 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