The Rac GTPase effector p21-activated kinase is essential for hematopoietic stem/progenitor cell migration and engraftment

Dorrance, Adrienne M., De Vita, Serena, Radu, Maria, Reddy, Pavankumar N. G., McGuinness, Meaghan K., Harris, Chad E., Mathieu, Ronald, Lane, Steven W., Kosoff, Rachelle, Milsom, Michael D., Chernoff, Jonathan and Williams, David A. (2013) The Rac GTPase effector p21-activated kinase is essential for hematopoietic stem/progenitor cell migration and engraftment. Blood, 121 13: 2474-2482. doi:10.1182/blood-2012-10-460709


Author Dorrance, Adrienne M.
De Vita, Serena
Radu, Maria
Reddy, Pavankumar N. G.
McGuinness, Meaghan K.
Harris, Chad E.
Mathieu, Ronald
Lane, Steven W.
Kosoff, Rachelle
Milsom, Michael D.
Chernoff, Jonathan
Williams, David A.
Title The Rac GTPase effector p21-activated kinase is essential for hematopoietic stem/progenitor cell migration and engraftment
Journal name Blood   Check publisher's open access policy
ISSN 1528-0020
0006-4971
Publication date 2013-03-28
Sub-type Article (original research)
DOI 10.1182/blood-2012-10-460709
Open Access Status Not Open Access
Volume 121
Issue 13
Start page 2474
End page 2482
Total pages 9
Place of publication Washington, DC United States
Publisher American Society of Hematology
Language eng
Formatted abstract
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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