Disruption of a single Pten allele augments the chemotactic response of B lymphocytes to stromal cell-derived factor-1.
The tumor suppressor, Pten, has emerged as a critical negative regulator of phosphatidylinositol-3-kinase-dependent intracellular signaling pathways responsible for phenomena such as cellular adhesion, proliferation, and apoptosis. Herein, we present evidence that Pten regulates chemokine-dependent events in B lymphocytes. Primary B cells isolated from Pten(+/-) mice demonstrated increased responsiveness to stromal cell-derived factor-1-induced chemotaxis. This was accompanied by an elevated level of protein kinase B phosphorylation on Ser(473). Our results suggest not only that Pten may be an important regulator of stromal cell-derived factor-1-directed chemotaxis, but also that Pten heterozygosity is associated with increased cellular sensitivity to this chemokine, likely via dysregulation of events lying downstream of phosphatidylinositol-3-kinase. These observations suggest a mechanism by which loss of a single Pten allele may confer a selective advantage on cells during multistep tumor progression.
Fox
Joanne A
JA
Center for Molecular Medicine and Therapeutics, British Columbia Research Institute for Children's and Women's Health, and Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Ung
Karen
K
Tanlimco
Sonia G
SG
Jirik
Frank R
FR
D000276:Adjuvants, Immunologic / Q000235:genetics* / Q000502:physiology; D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006580:Genetic Carrier Screening; D051379:Mice; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017154:Stromal Cells / Q000201:enzymology / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D000276:Adjuvants, Immunologic; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase