Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
J Biol Chem. 2012 Mar 30;287(14):11037-48. doi: 10.1074/jbc.M111.310946. Epub 2012 Feb 10.
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.
造血祖细胞激酶 1（HPK1）是一种 Ste20 样丝氨酸/苏氨酸激酶，可抑制免疫反应和自身免疫。B 细胞受体（BCR）信号通过诱导 BLNK/HPK1 相互作用激活 HPK1。BCR 信号转导过程中 HPK1 是否可以反过来调节 BLNK 尚不清楚。在这里，我们发现，当 BCR 被交联时，缺乏 HPK1 的 B 细胞显示出过度增殖和 IκB 激酶和 MAPKs（ERK、p38 和 JNK）的过度激活。HPK1 通过诱导 BLNK 苏氨酸 152 磷酸化来减弱 BCR 诱导的细胞激活，这介导了 BLNK/14-3-3 的结合。此外，磷酸化的 BLNK 苏氨酸 152 残基在赖氨酸残基 37、38 和 42 上发生泛素化，导致 BCR 信号转导过程中 MAPK 和 IκB 激酶激活的减弱。这些结果揭示了 HPK1 介导的磷酸化、泛素化和随后的激活 BLNK 降解对 BCR 信号转导的一种新的负反馈调节。
