HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion.

<h4>Background</h4>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-p...

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Autores principales:	Sebastian Königsberger, Doris Peckl-Schmid, Nadja Zaborsky, Irene Patzak, Friedemann Kiefer, Gernot Achatz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b50c7e23cadc4b17b2bb1867c68e8751
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spelling	oai:doaj.org-article:b50c7e23cadc4b17b2bb1867c68e87512021-11-18T06:35:31ZHPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion.1932-620310.1371/journal.pone.0012468https://doaj.org/article/b50c7e23cadc4b17b2bb1867c68e87512010-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20824186/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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 NFkappaB-mediated gene transcription in T-cells, the function of HPK1 in B-cells to date remains rather ill-defined.<h4>Methodology/principal findings</h4>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 integrin activity is caused downstream of Src, by a signalling module independent of PI3K and PLC, involving HPK1, SKAP55 homologue (SKAP-HOM) and Rap1-GTP-interacting adaptor molecule (RIAM). This alters actin dynamics and renders focal adhesion kinase (FAK) constitutively phosphorylated. Bone marrow and splenic B-cell development of HPK1(-/-) mice are largely unaffected, except age-related tendencies for increased splenic cellularity and BCR downregulation. In addition, naïve splenic knockout B-cells appear hyperresponsive to a range of stimuli applied ex vivo as recently demonstrated by others for T-cells.<h4>Conclusions/significance</h4>We therefore conclude that HPK1 exhibits a dual function in B-cells by negatively regulating integrin activity and controlling cellular activation, which makes it an interesting candidate to study in pathological settings like autoimmunity and cancer.Sebastian KönigsbergerDoris Peckl-SchmidNadja ZaborskyIrene PatzakFriedemann KieferGernot AchatzPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 9 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sebastian Königsberger Doris Peckl-Schmid Nadja Zaborsky Irene Patzak Friedemann Kiefer Gernot Achatz HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion.
description	<h4>Background</h4>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 NFkappaB-mediated gene transcription in T-cells, the function of HPK1 in B-cells to date remains rather ill-defined.<h4>Methodology/principal findings</h4>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 integrin activity is caused downstream of Src, by a signalling module independent of PI3K and PLC, involving HPK1, SKAP55 homologue (SKAP-HOM) and Rap1-GTP-interacting adaptor molecule (RIAM). This alters actin dynamics and renders focal adhesion kinase (FAK) constitutively phosphorylated. Bone marrow and splenic B-cell development of HPK1(-/-) mice are largely unaffected, except age-related tendencies for increased splenic cellularity and BCR downregulation. In addition, naïve splenic knockout B-cells appear hyperresponsive to a range of stimuli applied ex vivo as recently demonstrated by others for T-cells.<h4>Conclusions/significance</h4>We therefore conclude that HPK1 exhibits a dual function in B-cells by negatively regulating integrin activity and controlling cellular activation, which makes it an interesting candidate to study in pathological settings like autoimmunity and cancer.
format	article
author	Sebastian Königsberger Doris Peckl-Schmid Nadja Zaborsky Irene Patzak Friedemann Kiefer Gernot Achatz
author_facet	Sebastian Königsberger Doris Peckl-Schmid Nadja Zaborsky Irene Patzak Friedemann Kiefer Gernot Achatz
author_sort	Sebastian Königsberger
title	HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion.
title_short	HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion.
title_full	HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion.
title_fullStr	HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion.
title_full_unstemmed	HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion.
title_sort	hpk1 associates with skap-hom to negatively regulate rap1-mediated b-lymphocyte adhesion.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/b50c7e23cadc4b17b2bb1867c68e8751
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HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion.

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