cAMP-induced PKCzeta activation increases functional CXCR4 expression on human CD34+ hematopoietic progenitors.
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 PKCzeta activity. CXCR4 expression and PKCzeta 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 PKCzeta 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 PKCzeta-dependent manner. cAMP- and TNFalpha-stimulated pathways converged in PKCzeta-activated CXCR4 expression and MMP-2/MMP-9 secretion. cAMP treatment had a beneficial effect on CD34+ cell survival in a PKCzeta-mediated fashion. Taken together, our data reveal major roles for cAMP-induced PKCzeta activation in signaling governing the motility and development of CD34+ cells.
Goichberg
Polina
P
Immunology Department, The Weizmann Institute of Science, Rehovot, Israel.
Kalinkovich
Alexander
A
Borodovsky
Nataliya
N
Tesio
Melania
M
Petit
Isabelle
I
Nagler
Arnon
A
Hardan
Izhar
I
Lapidot
Tsvee
T
D000328:Adult; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003563:Cyclic CMP / Q000031:analogs & derivatives / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010120:Oxytocics / Q000494:pharmacology; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013154:Spleen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D018952:Antigens, CD34; D010120:Oxytocics; C107953:RAC1 protein, human; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha; D001613:beta 2-Microglobulin; D003563:Cyclic CMP; C053441:dibutyryl cyclic-3',5'-cytidine monophosphate; D051744:Protein Kinase C-epsilon; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020830:rac1 GTP-Binding Protein; D020827:rap1 GTP-Binding Proteins; D015232:Dinoprostone