hpk1 associates with skap-hom to negatively regulate rap1-mediated b-lymphocyte adhesion与skap-hom hpk1 associates负调控rap1-mediated淋巴球附着力.pdfVIP

HPK1 Associates with SKAP-HOM to Negatively Regulate Rap1-Mediated B-Lymphocyte Adhesion ¨ 1 1 1 2 3 Sebastian Konigsberger , Doris Peckl-Schmid , Nadja Zaborsky , Irene Patzak , Friedemann Kiefer , Gernot Achatz1* 1 Department of Molecular Biology, University of Salzburg, Salzburg, Austria,, 2 Lincoln’s Inn Fields Laboratories, Cancer Research UK London Research Institute, London, ¨ United Kingdom,, 3 Department Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Munster, Germany Abstract Background: Hematopoietic progenitor kinase 1 (HPK1) is a Ste20-related serine/threonine kinase activated by a range of environmental stimuli including genotoxic stress, growth factors, inflammatory cytokines and antigen receptor triggering. Being inducibly recruited to membrane-proximal signalling scaffolds to regulate NFAT, AP-1 and NFkB-mediated gene transcription in T-cells, the function of HPK1 in B-cells to date remains rather ill-defined. Methodology/Principal Findings: By using two loss of function models, we show that HPK1 displays a novel function in regulating B-cell integrin activity. Wehi 231 lymphoma cells lacking HPK1 after shRNA mediated knockdown exhibit increased basic activation levels of Ras-related protein 1 (Rap1), accompanied by a severe lymphocyte function-associated antigen-1 (LFA-1) dependent homotypic aggregation and increased adhesion to intercellular adhesion molecule 1 (ICAM-1). The observed phenotype of enhanced inte