Down-regulation of B cell receptor signaling by hematopoietic progenitor kinase 1 (HPK1)-mediated phosphorylation and ubiquitination of activated B cell linker protein (BLNK).

The Journal of Biological Chemistry
Xiaohong WangTse-Hua Tan

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.

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Citations

Jun 25, 2014·Proceedings of the National Academy of Sciences of the United States of America·Margaret K Seeley-FallenWenxia Song
Oct 15, 2013·Immunological Reviews·Wenxia SongArpita Upadhyaya
Jan 30, 2015·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Elias HobeikaDavid Medgyesi
Jul 7, 2016·The International Journal of Biochemistry & Cell Biology·Dara K MohammadC I Edvard Smith
Apr 12, 2018·The New England Journal of Medicine·Roland SchmitzLouis M Staudt
Jun 20, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Chia-Yu YangTse-Hua Tan
Sep 14, 2017·Molecular Medicine Reports·Qing ZhangHuilin Zhang
Jan 5, 2018·Oncotarget·Dara K MohammadC I Edvard Smith
Sep 9, 2020·ELife·Sansana Sawasdikosol, Steven Burakoff
Jan 10, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Chia-Yu YangTse-Hua Tan
Oct 24, 2019·Journal of Biomedical Science·Huai-Chia Chuang, Tse-Hua Tan
Nov 12, 2020·Journal of Structural Biology·Lorenzo SoiniChristian Ottmann

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