title: R-Ras and Rac GTPase cross-talk regulates hematopoietic progenitor cell migration, homing, and mobilization.
abstract: Adult hematopoietic progenitor cells (HPCs) are maintained by highly coordinated signals in the bone marrow. The molecular mechanisms linking intracellular signaling network of HPCs with their microenvironment remain poorly defined. The Rho family GTPase Rac1/Rac2 has previously been implicated in cell functions involved in HPC maintenance, including adhesion, migration, homing, and mobilization. In the present studies we have identified R-Ras, a member of the Ras family, as a key signal mediator required for Rac1/Rac2 activation. We found that whereas Rac1 activity is up-regulated upon stem cell factor, integrin, or CXCL12 stimulation, R-Ras activity is inversely up-regulated. Expression of a constitutively active R-Ras mutant resulted in down-regulation of Rac1-activity whereas deletion of R-Ras led to an increase in Rac1/Rac2 activity and signaling. R-Ras(-/-) HPCs displayed a constitutively assembled cortical actin structure and showed increased directional migration. Rac1/Rac2 inhibition reversed the migration phenotype of R-Ras(-/-) HPCs, similar to that by expressing an R-Ras active mutant. Furthermore, R-Ras(-/-) mice showed enhanced responsiveness to G-CSF for HPC mobilization and exhibited decreased bone marrow homing. Transplantation experiments indicate that the R-Ras deficiency-induced HPC mobilization is a HPC intrinsic property. These results indicate that R-Ras is a critical regulator of Rac signaling required for HPC migration, homing, and mobilization.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Shang
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
authors.forename: Lina
authors.initials: L
authors.lastname: Li
authors.forename: Fukun
authors.initials: F
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: James F
authors.initials: JF
authors.lastname: Johnson
authors.forename: Ashley
authors.initials: A
authors.lastname: Ficker
authors.forename: Deidre
authors.initials: D
authors.lastname: Daria
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D053687:Adult Stem Cells / Q000166:cytology / Q000201:enzymology; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000199:Actins; D009479:Neuropeptides; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse; C513254:Rras protein, mouse