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* Department of Microbiology and Immunology,
Walther Oncology Center, and
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; and
Walther Cancer Institute, Indianapolis, IN 46202
Migration of hemopoietic stem and progenitor cells (HSPC) is required for homing to bone marrow following transplantation. Therefore, it is critical to understand signals underlying directional movement of HSPC. Stromal cell-derived factor-1 (SDF-1)/CXCL12 is a potent chemoattractant for HSPC. In this study, we demonstrate that the serine-threonine protein phosphatase (PP)2A plays an important role in regulation of optimal level and duration of Akt/protein kinase B activation (a molecule important for efficient chemotaxis), in response to SDF-1. Inhibition of PP2A, using various pharmacological inhibitors of PP2A including okadaic acid (OA) as well as using genetic approaches including dominant-negative PP2A-catalytic subunit (PP2A-C) or PP2A-C small interfering RNA, in primary CD34+ cord blood (CB) cells led to reduced chemotaxis. This was associated with impairment in polarization and slower speed of movement in response to SDF-1. Concomitantly, SDF-1-induced Akt phosphorylation was robust and prolonged. Following SDF-1 stimulation, Akt and PP2A-C translocate to plasma membrane with enhanced association of PP2A-C with Akt observed at the plasma membrane. Inhibition of PI3K by low-dose LY294002 partially recovered chemotactic activity of cells pretreated with OA. In addition to chemotaxis, adhesion of CD34+ cells to fibronectin was impaired by OA pretreatment. Our study demonstrates PP2A plays an important role in chemotaxis and adhesion of CD34+ CB cells in response to SDF-1. CD34+ CB cells pretreated with OA showed impaired ability to repopulate NOD-SCID mice in vivo, suggesting physiological relevance of these observations.
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.
1 These studies were supported by U.S. Public Health Service Grants RO1 HL 67384 and RO1 HL 56416 and a project in PO1 HL053586 to H.E.B.
2 Address correspondence and reprint requests to Dr. Sunanda Basu, Walther Oncology Center, Indiana University School of Medicine, Research Institute No. 2 Building, Room 302, 950 West Walnut Street, Indianapolis, IN 46202-5181. E-mail address: sunbasu{at}iupui.edu
3 Abbreviations used in this paper: CB, cord blood; CAAkt, constitutively active Akt; DNPP2A-C, dominant-negative mutant of protein phosphatase 2A-catalytic subunit; GPCR, G protein-coupled receptor; GSK, glycogen synthase kinase; HSPC, hemopoietic stem and progenitor cell; OA, okadaic acid; PH, pleckstrin homology; PKB, protein kinase B; PP, protein phosphatase; PP2A-C, PP2A-catalytic subunit; PTEN, phosphatase and tensin homologue; SDF-1, stromal cell-derived factor-1; siRNA, small interfering RNA; WT, wild type.
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