Kiefer F, Tibbles L A, Anafi M, Janssen A, Zanke B W, Lassam N, Pawson T, Woodgett J R, Iscove N N
Department of Medical Biophysics, University of Toronto, Ontario, Canada.
EMBO J. 1996 Dec 16;15(24):7013-25.
In mammalian cells, a specific stress-activated protein kinase (SAPK/JNK) pathway is activated in response to inflammatory cytokines, injury from heat, chemotherapeutic drugs and UV or ionizing radiation. The mechanisms that link these stimuli to activation of the SAPK/JNK pathway in different tissues remain to be identified. We have developed and applied a PCR-based subtraction strategy to identify novel genes that are differentially expressed at specific developmental points in hematopoiesis. We show that one such gene, hematopoietic progenitor kinase 1 (hpk1), encodes a serine/threonine kinase sharing similarity with the kinase domain of Ste20. HPK1 specifically activates the SAPK/JNK pathway after transfection into COS1 cells, but does not stimulate the p38/RK or mitogen-activated ERK signaling pathways. Activation of SAPK requires a functional HPK1 kinase domain and HPK1 signals via the SH3-containing mixed lineage kinase MLK-3 and the known SAPK activator SEK1. HPK1 therefore provides an example of a cell type-specific input into the SAPK/JNK pathway. The developmental specificity of its expression suggests a potential role in hematopoietic lineage decisions and growth regulation.
在哺乳动物细胞中，一种特定的应激激活蛋白激酶（SAPK/JNK）通路会在受到炎性细胞因子、热损伤、化疗药物以及紫外线或电离辐射的刺激时被激活。然而，在不同组织中将这些刺激与SAPK/JNK通路激活联系起来的机制仍有待确定。我们开发并应用了一种基于PCR的消减策略，以鉴定在造血过程中特定发育阶段差异表达的新基因。我们发现，其中一个名为造血祖细胞激酶1（hpk1）的基因，编码一种与Ste20激酶结构域具有相似性的丝氨酸/苏氨酸激酶。将HPK1转染到COS1细胞后，它能特异性激活SAPK/JNK通路，但不会刺激p38/RK或丝裂原激活的ERK信号通路。SAPK的激活需要一个功能性的HPK1激酶结构域，并且HPK1通过含有SH3结构域的混合谱系激酶MLK-3和已知的SAPK激活剂SEK1来传递信号。因此，HPK1为SAPK/JNK通路提供了一个细胞类型特异性输入的例子。其表达的发育特异性表明它在造血谱系决定和生长调节中可能发挥作用。
