HPK1, a Hematopoietic Protein Kinase Activating the SAPK/JNK Pathway

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 1996 Dec 16

PMID 9003777

Citations 62

Authors

F Kiefer

L A Tibbles

M Anafi

A Janssen

B W Zanke

N Lassam

T Pawson

J R Woodgett

N N Iscove

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

HPK1 kinase inhibitor: a sufficient approach to target HPK1 to modulate T cell activation in cancer immunotherapy compared with degraders.

Wang Q, Zhu X, Li J, Xu S, Wang A, Zhang X Front Immunol. 2025; 16:1449106.

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An updated review of small-molecule HPK1 kinase inhibitors (2016-present).

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Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.

Ou X, Gao G, Habaz I, Wang Y MedComm (2020). 2024; 5(9):e694.

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HPK1 Dysregulation-Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression.

Choi W, Kwon H, Yi E, Lee H, Kim J, Park H Adv Sci (Weinh). 2024; 11(29):e2400920.

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