The Rac GTPase effector p21-activated kinase is essential for hematopoietic stem/progenitor cell migration and engraftment
In: Blood, Jg. 121 (2013-03-28), S. 2474-2482
Online
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Zugriff:
The p21-activated kinases (Paks) are serine/threonine kinases that are major effectors of the Rho guanosine 5'\x{2011}triphosphatase, Rac, and Cdc42. Rac and Cdc42 are known regulators of hematopoietic stem and progenitor cell (HSPC) function, however, a direct role for Paks in HSPCs has yet to be elucidated. Lin(-)Sca1(+)c-kit(+) (LSK) cells from wild-type mice were transduced with retrovirus expressing Pak inhibitory domain (PID), a well-characterized inhibitor of Pak activation. Defects in marrow homing and in vitro cell migration, assembly of the actin cytoskeleton, proliferation, and survival were associated with engraftment failure of PID-LSK. The PID-LSK demonstrated decreased phosphorylation of extracellular signal-regulated kinase (ERK), whereas constitutive activation of ERK in these cells led to rescue of hematopoietic progenitor cell proliferation in vitro and partial rescue of Pak-deficient HSPC homing and engraftment in vivo. Using conditional knock-out mice, we demonstrate that among group A Paks, Pak2(-/-) HSPC show reduced homing to the bone marrow and altered cell shape similar to PID-LSK cells in vitro and are completely defective in HSPC engraftment. These data demonstrate that Pak proteins are key components of multiple engraftment-associated HSPC functions and play a direct role in activation of ERK in HSPCs, and that Pak2 is specifically essential for HSPC engraftment.
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The Rac GTPase effector p21-activated kinase is essential for hematopoietic stem/progenitor cell migration and engraftment
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Autor/in / Beteiligte Person: | Milsom, Michael D. ; Mathieu, Ronald ; Kosoff, Rachelle ; Reddy, Pavankumar N. G. ; Dorrance, Adrienne M. ; Harris, Chad E. ; Serena De Vita ; Lane, Steven W. ; Chernoff, Jonathan ; McGuinness, Meaghan ; Williams, David A. ; Radu, Maria |
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Zeitschrift: | Blood, Jg. 121 (2013-03-28), S. 2474-2482 |
Veröffentlichung: | American Society of Hematology, 2013 |
Medientyp: | unknown |
ISSN: | 1528-0020 (print) ; 0006-4971 (print) |
DOI: | 10.1182/blood-2012-10-460709 |
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