title: Down-regulation of B cell receptor signaling by hematopoietic progenitor kinase 1 (HPK1)-mediated phosphorylation and ubiquitination of activated B cell linker protein (BLNK).
abstract: Hematopoietic progenitor kinase 1 (HPK1) is a Ste20-like serine/threonine kinase that suppresses immune responses and autoimmunity. B cell receptor (BCR) signaling activates HPK1 by inducing BLNK/HPK1 interaction. Whether HPK1 can reciprocally regulate BLNK during BCR signaling is unknown. Here, we show that HPK1-deficient B cells display hyper-proliferation and hyper-activation of IκB kinase and MAPKs (ERK, p38, and JNK) upon the ligation of BCR. HPK1 attenuates BCR-induced cell activation via inducing BLNK threonine 152 phosphorylation, which mediates BLNK/14-3-3 binding. Furthermore, threonine 152-phosphorylated BLNK is ubiquitinated at lysine residues 37, 38, and 42, leading to attenuation of MAPK and IκB kinase activation in B cells during BCR signaling. These results reveal a novel negative feedback regulation of BCR signaling by HPK1-mediated phosphorylation, ubiquitination, and subsequent degradation of the activated BLNK.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Ju-Pi
authors.initials: JP
authors.lastname: Li
authors.forename: Hui-Kai
authors.initials: HK
authors.lastname: Kuo
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Chiu
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Dement
authors.forename: Joung-Liang
authors.initials: JL
authors.lastname: Lan
authors.forename: Der-Yuan
authors.initials: DY
authors.lastname: Chen
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Yang
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
authors.forename: Tse-Hua
authors.initials: TH
authors.lastname: Tan
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D001665:Binding Sites; D015536:Down-Regulation; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D011947:Receptors, Antigen, B-Cell; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex