Atypical PKC-zeta regulates SDF-1-mediated migration and development of human CD34+ progenitor cells.
The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, play a major role in migration, retention, and development of hematopoietic progenitors in the bone marrow. We report the direct involvement of atypical PKC-zeta in SDF-1 signaling in immature human CD34(+)-enriched cells and in leukemic pre-B acute lymphocytic leukemia (ALL) G2 cells. Chemotaxis, cell polarization, and adhesion of CD34(+) cells to bone marrow stromal cells were found to be PKC-zeta dependent. Overexpression of PKC-zeta in G2 and U937 cells led to increased directional motility to SDF-1. Interestingly, impaired SDF-1-induced migration of the pre-B ALL cell line B1 correlated with reduced PKC-zeta expression. SDF-1 triggered PKC-zeta phosphorylation, translocation to the plasma membrane, and kinase activity. Furthermore we identified PI3K as an activator of PKC-zeta, and Pyk-2 and ERK1/2 as downstream targets of PKC-zeta. SDF-1-induced proliferation and MMP-9 secretion also required PKC-zeta activation. Finally, we showed that in vivo engraftment, but not homing, of human CD34(+)-enriched cells to the bone marrow of NOD/SCID mice was PKC-zeta dependent and that injection of mice with inhibitory PKC-zeta pseudosubstrate peptides resulted in mobilization of murine progenitors. Our results demonstrate a central role for PKC-zeta in SDF-1-dependent regulation of hematopoietic stem and progenitor cell motility and development.
Petit
Isabelle
I
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Goichberg
Polina
P
Spiegel
Asaf
A
Peled
Amnon
A
Brodie
Chaya
C
Seger
Rony
R
Nagler
Arnon
A
Alon
Ronen
R
Lapidot
Tsvee
T
D000199:Actins / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D000099221:Protein Kinase C zeta
D000199:Actins; D018952:Antigens, CD34; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D000099221:Protein Kinase C zeta; C515255:CXCL12 protein, human; C515256:Cxcl12 protein, mouse