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

Adrienne M Dorrance1, Serena De Vita, Maria Radu

  • 1Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.

Blood
|January 22, 2013
PubMed

Insights

Paks are crucial for hematopoietic stem cell function, impacting migration, proliferation, and survival. Pak2 is essential for successful bone marrow engraftment and regulates extracellular signal-regulated kinase (ERK) activation.

Area of Science:

  • Cell Biology
  • Hematopoiesis
  • Molecular Signaling

Background:

  • Paks are serine/threonine kinases downstream of Rac and Cdc42 GTPases.
  • Rac and Cdc42 regulate hematopoietic stem and progenitor cell (HSPC) function.
  • The direct role of Paks in HSPCs remains unclear.

Purpose of the Study:

  • To investigate the role of Paks in HSPC function, including homing, migration, proliferation, survival, and engraftment.
  • To elucidate the relationship between Pak activity and extracellular signal-regulated kinase (ERK) signaling in HSPCs.
  • To determine the specific contribution of Pak2 to HSPC engraftment.

Main Methods:

  • Retroviral transduction of wild-type mouse Lin(-)Sca1(+)c-kit(+) (LSK) cells with a Pak inhibitory domain (PID).
  • Assessment of marrow homing, in vitro cell migration, actin cytoskeleton assembly, proliferation, and survival.
  • Analysis of extracellular signal-regulated kinase (ERK) phosphorylation.
  • Use of conditional knock-out mice lacking Pak2 in HSPCs.

Main Results:

  • PID-transduced LSK cells exhibited defects in homing, migration, cytoskeleton assembly, proliferation, and survival, leading to engraftment failure.
  • PID-LSK cells showed decreased ERK phosphorylation; constitutive ERK activation rescued proliferation and partially rescued homing and engraftment.
  • Pak2(-/-) HSPCs displayed reduced homing, altered cell shape, and complete defect in engraftment.

Conclusions:

  • Pak proteins are essential for multiple HSPC functions critical for engraftment.
  • Paks directly regulate ERK activation in HSPCs.
  • Pak2 is indispensable for successful HSPC engraftment in vivo.

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