| First Author | Reddy PN | Year | 2016 |
| Journal | Blood | Volume | 127 |
| Issue | 16 | Pages | 1967-75 |
| PubMed ID | 26932803 | Mgi Jnum | J:233013 |
| Mgi Id | MGI:5780611 | Doi | 10.1182/blood-2016-01-693572 |
| Citation | Reddy PN, et al. (2016) p21-activated kinase 2 regulates HSPC cytoskeleton, migration, and homing via CDC42 activation and interaction with beta-Pix. Blood 127(16):1967-75 |
| abstractText | Cytoskeletal remodeling of hematopoietic stem and progenitor cells (HSPCs) is essential for homing to the bone marrow (BM). The Ras-related C3 botulinum toxin substrate (Rac)/cell division control protein 42 homolog (CDC42) effector p21-activated kinase (Pak2) has been implicated in HSPC homing and engraftment. However, the molecular pathways mediating Pak2 functions in HSPCs are unknown. Here, we demonstrate that both Pak2 kinase activity and its interaction with the PAK-interacting exchange factor-beta (beta-Pix) are required to reconstitute defective ITALIC! Pak2 (ITALIC! Delta/Delta)HSPC homing to the BM. Pak2 serine/threonine kinase activity is required for stromal-derived factor-1 (SDF1alpha) chemokine-induced HSPC directional migration, whereas Pak2 interaction with beta-Pix is required to regulate the velocity of HSPC migration and precise F-actin assembly. Lack of SDF1alpha-induced filopodia and associated abnormal cell protrusions seen in ITALIC! Pak2 (ITALIC! Delta/Delta)HSPCs were rescued by wild-type (WT) Pak2 but not by a Pak2-kinase dead mutant (KD). Expression of a beta-Pix interaction-defective mutant of Pak2 rescued filopodia formation but led to abnormal F-actin bundles. Although CDC42 has previously been considered an upstream regulator of Pak2, we found a paradoxical decrease in baseline activation of CDC42 in ITALIC! Pak2 (ITALIC! Delta/Delta)HSPCs, which was rescued by expression of Pak2-WT but not by Pak2-KD; defective homing of ITALIC! Pak2-deleted HSPCs was rescued by constitutive active CDC42. These data demonstrate that both Pak2 kinase activity and its interaction with beta-Pix are essential for HSPC filopodia formation, cytoskeletal integrity, and homing via activation of CDC42. Taken together, we provide mechanistic insights into the role of Pak2 in HSPC migration and homing. |
