Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade
Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade
复制标题
DOI：
10.1101/gad.10.18.2251
复制
发表时间：
1996-09-15
影响因子：
10.5
通讯作者：
Tan, TH
中科院分区：
文献类型：
--
作者：
Hu, MCT;Qiu, WR;Tan, TH
c-Jun氨基末端激酶（JNKs）/应激激活蛋白激酶（SAPKs）在哺乳动物细胞的应激反应中起着至关重要的作用。造血系统中这一通路的机制尚不清楚，但它是理解血细胞分化分子基础的关键。我们克隆了一种新的蛋白激酶，称为造血祖细胞激酶1（HPK 1），主要在造血细胞，包括早期祖细胞中表达。HPK 1与p21（Cdc 42/Rac 1）激活的激酶（PAK）和参与丝裂原激活蛋白激酶（MAPK）级联的酵母STE 20有较远的关系。HPK 1的表达特异性地激活JNK 1，并且其在体内强烈地提高AP-1介导的转录活性。HPK 1直接结合并磷酸化MEKK 1，而JNK 1被HPK 1激活被显性负性MEKK 1或MKK 4/SEK突变体抑制。有趣的是，与PAK 65不同，HPK 1不包含小的GTdR Rac 1/Cdc 42结合结构域，也不与Rac 1或Cdc 42结合，这表明HPK 1的激活是Rac 1/Cdc 42独立的。这些结果表明HPK 1是JNK/SAPK信号通路的新功能激活剂。
The c-Jun amino-terminal kinases (JNKs)/stress-activated protein kinases (SAPKs) play a crucial role in stress responses in mammalian cells. The mechanism underlying this pathway in the hematopoietic system is unclear, but it is a key in understanding the molecular basis of blood cell differentiation. We have cloned a novel protein kinase, termed hematopoietic progenitor kinase 1 (HPK1), that is expressed predominantly in hematopoietic cells, including early progenitor cells. HPK1 is related distantly to the p21(Cdc42/Rac1)-activated kinase (PAK) and yeast STE20 implicated in the mitogen-activated protein kinase (MAPK) cascade. Expression of HPK1 activates JNK1 specifically, and it elevates strongly AP-1-mediated transcriptional activity in vivo. HPK1 binds and phosphorylates MEKK1 directly, whereas JNK1 activation by HPK1 is inhibited by a dominant-negative MEKK1 or MKK4/SEK mutant. Interestingly, unlike PAK65, HPK1 does not contain the small GTPase Rac1/Cdc42-binding domain and does not bind to either Rac1 or Cdc42, suggesting that HPK1 activation is Rac1/Cdc42-independent. These results indicate that HPK1 is a novel functional activator of the JNK/SAPK signaling pathway.