title: The Rac GTPase effector p21-activated kinase is essential for hematopoietic stem/progenitor cell migration and engraftment.
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.
authors: Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.
authors: Adrienne M
authors: AM
authors: Dorrance
authors: Serena
authors: S
authors: De Vita
authors: Maria
authors: M
authors: Radu
authors: Pavankumar N G
authors: PN
authors: Reddy
authors: Meaghan K
authors: MK
authors: McGuinness
authors: Chad E
authors: CE
authors: Harris
authors: Ronald
authors: R
authors: Mathieu
authors: Steven W
authors: SW
authors: Lane
authors: Rachelle
authors: R
authors: Kosoff
authors: Michael D
authors: MD
authors: Milsom
authors: Jonathan
authors: J
authors: Chernoff
authors: David A
authors: DA
authors: Williams
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics* / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D054462:p21-Activated Kinases / Q000235:genetics / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology
chemical_list: D054462:p21-Activated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020744:rac GTP-Binding Proteins