Hematopoietic Progenitor Kinase 1 Is a Component of Transforming Growth Factor β-induced c-Jun N-terminal Kinase Signaling Cascade

Guisheng Zhou,Susan C Lee,Zhengbin Yao,Tse-Hua Tan

doi:10.1074/jbc.274.19.13133

Guisheng Zhou, Susan C Lee + Show 2 more

Open Access

https://doi.org/10.1074/jbc.274.19.13133

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Abstract

The c-Jun N-terminal kinase (JNK) signaling pathway is involved in transforming growth factor beta (TGF-beta) signaling in a variety of cell systems. We report here that hematopoietic progenitor kinase 1 (HPK1), a novel Ste20-like protein serine/threonine kinase, serves as an upstream mediator for the TGF-beta-activated JNK1 cascade in 293T cells. TGF-beta treatment resulted in a time-dependent activation of HPK1, which was accompanied by similar kinetics of JNK1 activation. The activation of JNK1 by TGF-beta was abrogated by a kinase-defective HPK1 mutant but not by a kinase-defective mutant of kinase homologous to Ste20/Sps1. This result indicates that HPK1 is specifically required for TGF-beta-induced activation of JNK1. We also found that TGF-beta-induced JNK1 activation was blocked by a kinase-defective mutant of TGF-beta-activated kinase 1 (TAK1). In addition, interaction between HPK1 and TAK1 was observed in transient transfection assays, and this interaction was enhanced by TGF-beta treatment. Both stress-activated protein kinase/extracellular signal-regulated kinase kinase (SEK) and mitogen-activated protein kinase kinase 7 (MKK7) are immediate upstream activators of JNK1. Although SEK and MKK7 acted downstream of TAK1, only a kinase-defective SEK mutant blocked TGF-beta-induced activation of JNK1, indicating that the TGF-beta signal is relayed solely through SEK, but not MKK7, in vivo. Furthermore, TGF-beta-induced activating protein 1 activation was blocked by a HPK1 mutant, as well as by TAK1 and SEK mutants. Taken together, these studies establish a potential cascade of TGF-beta-activated interacting kinases beginning with HPK1, a Ste20 homolog, and ending in JNK1 activation: HPK1 --> TAK1 --> SEK --> JNK1.

Highlights

Transforming growth factor-␤ (TGF-␤)1 belongs to a family of multifunctional cytokines that regulate cell proliferation, cel
We have previously demonstrated that TGF-␤-activated kinase 1 (TAK1), a TGF␤-activated kinase, is a potent activator for Jun N-terminal kinase (JNK) and serves downstream of hematopoietic progenitor kinase 1 (HPK1), a MAPKKK kinase (MAPKKKK) level kinase, in the JNK pathway [10]
There is a growing interest in the identification and characterization of Ste20-like kinases, because they might represent the first step in a number of linear cascades of sequentially acting serine/threonine kinases leading to the stimulation of members of the mitogen-activated protein kinase (MAPK) superfamily

Summary

Introduction

Transforming growth factor-␤ (TGF-␤)1 belongs to a family of multifunctional cytokines that regulate cell proliferation, cel-. We have previously shown in transfected 293T cells that TAK1, a TGF-␤-activated MAPKKK level kinase, serves downstream of HPK1 and upstream of SEK in the JNK pathway [10]. These studies establish that HPK1 acts as an upstream activator for the TAK1-SEK-JNK1 module in relaying the TGF-␤ signal into the nuclei in 293T cells.

Results

Conclusion