Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation
Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation
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DOI：
10.1038/sj.cdd.4402042
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发表时间：
2007-03-01
影响因子：
12.4
通讯作者：
Kiefer, F.
中科院分区：
文献类型：
--
作者：
Arnold, R.;Frey, C. R.;Kiefer, F.
我们研究了原代小鼠祖细胞的单核细胞分化，以了解分化的分子机制。我们发现与分化相关的 caspase-3 的严格控制的非凋亡激活。尽管在单核细胞分化过程中已检测到 caspase 活性，但尚未确定 caspase-3 靶标。我们发现造血祖激酶 1 (HPK1) 在单核细胞分化过程中被加工成 N 端和 C 端片段。虽然 HPK1 是 T 细胞和 B 细胞中的一种免疫受体近端激酶，但它在骨髓细胞中的作用尚不清楚。在这里，我们证明 N 端裂解产物 HPK1-N（包含激酶结构域）赋予祖细胞独立于生长因子 IL-3 的存活能力。此外，HPK1-N 导致祖细胞向单核细胞谱系分化。与全长激酶相比，HPK1-N 具有组成型活性，导致 JNK 持续激活、磷酸化不良和存活。在小鼠原代祖细胞分化过程中阻断 caspase 活性会导致 HPK1-N 水平降低、JNK 活性受到抑制并减弱单核细胞分化。我们的工作通过 caspase 介导的 HPK1 向 HPK1-N 的加工解释了单核细胞分化过程中生长因子独立的存活。
We studied monocytic differentiation of primary mouse progenitor cells to understand molecular mechanisms of differentiation. We found a tightly controlled non-apoptotic activation of caspase-3 that correlated with differentiation. Although caspase activity was already detected during monocytic differentiation, a caspase-3 target has not been identified yet. We show that hematopoietic progenitor kinase 1 (HPK1) is processed towards its N- and C-terminal fragments during monocytic differentiation. While HPK1 is an immunoreceptor-proximal kinase in T and B cells, its role in myeloid cells is elusive. Here, we show that the N-terminal cleavage product, HPK1-N, comprising the kinase domain, confers progenitor cell survival independent of the growth factor IL-3. Furthermore, HPK1-N causes differentiation of progenitor cells towards the monocytic lineage. In contrast to full-length kinase, HPK1-N is constitutively active causing sustained JNK activation, Bad phosphorylation and survival. Blocking of caspase activity during differentiation of primary mouse progenitor cells leads to reduced HPK1-N levels, suppressed JNK activity and attenuated monocytic differentiation. Our work explains growth factor-independent survival during monocytic differentiation by caspase-mediated processing of HPK1 towards HPK1-N.