Ling P, Meyer C F, Redmond L P, Shui J W, Davis B, Rich R R, Hu M C, Wange R L, Tan T H
Department of Immunology and the Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
J Biol Chem. 2001 Jun 1;276(22):18908-14. doi: 10.1074/jbc.M101485200. Epub 2001 Mar 13.
Hematopoietic progenitor kinase 1 (HPK1), a mammalian Ste20-related serine/threonine protein kinase, is a hematopoietic-specific upstream activator of the c-Jun N-terminal kinase. Here, we provide evidence to demonstrate the involvement of HPK1 in T cell receptor (TCR) signaling. HPK1 was activated and tyrosine-phosphorylated with similar kinetics following TCR/CD3 or pervanadate stimulation. Co-expression of protein-tyrosine kinases, Lck and Zap70, with HPK1 led to HPK1 activation and tyrosine phosphorylation in transfected mammalian cells. Upon TCR/CD3 stimulation, HPK1 formed inducible complexes with the adapters Nck and Crk with different kinetics, whereas it constitutively interacted with the adapters Grb2 and CrkL in Jurkat T cells. Interestingly, HPK1 also inducibly associated with linker for activation of T cells (LAT) through its proline-rich motif and translocated into glycolipid-enriched microdomains (also called lipid rafts) following TCR/CD3 stimulation, suggesting a critical role for LAT in the regulation of HPK1. Together, these results identify HPK1 as a new component of TCR signaling. T cell-specific signaling molecules Lck, Zap70, and LAT play roles in the regulation of HPK1 during TCR signaling. Differential complex formation between HPK1 and adapters highlights the possible involvement of HPK1 in multiple signaling pathways in T cells.
造血祖细胞激酶1（HPK1）是一种与哺乳动物Ste20相关的丝氨酸/苏氨酸蛋白激酶，是c-Jun氨基末端激酶的造血特异性上游激活剂。在此，我们提供证据证明HPK1参与T细胞受体（TCR）信号传导。TCR/CD3或过氧钒酸盐刺激后，HPK1以相似的动力学被激活并发生酪氨酸磷酸化。蛋白酪氨酸激酶Lck和Zap70与HPK1共表达导致转染的哺乳动物细胞中HPK1激活和酪氨酸磷酸化。TCR/CD3刺激后，HPK1与衔接蛋白Nck和Crk以不同的动力学形成诱导性复合物，而在Jurkat T细胞中它与衔接蛋白Grb2和CrkL组成性相互作用。有趣的是，HPK1还通过其富含脯氨酸的基序与T细胞激活衔接蛋白（LAT）诱导性结合，并在TCR/CD3刺激后转位到富含糖脂的微结构域（也称为脂筏），提示LAT在HPK1的调节中起关键作用。总之，这些结果确定HPK1是TCR信号传导的一个新组分。T细胞特异性信号分子Lck、Zap70和LAT在TCR信号传导过程中对HPK1的调节起作用。HPK1与衔接蛋白之间不同的复合物形成突出了HPK1可能参与T细胞中的多种信号通路。
