Hematopoietic Kinase Modulation in T Cell Signaling

Hematopoietic progenitor kinase 1 (HPK1), a Ste20-like serine/threonine kinase, occupies a central role in tuning T cell receptor (TCR) signalling and downstream immune responses. By associating with adaptor proteins such as SLP-76 and LAT, HPK1 integrates proximal TCR inputs and engages MAP kinase pathways, notably JNK and ERK, to impose negative feedback on T cell activation. Domain–domain interactions between its kinase domain and a citron homology domain (CHD) stabilise HPK1 in an autoinhibited state, while post-translational modifications—including serine phosphorylation and ubiquitination of substrates—further attenuate signal propagation. Modulation of HPK1 activity has emerged as a promising strategy to enhance antitumour immunity by relieving intrinsic checkpoints within T cells and dendritic cells. Recent structural, genetic and pharmacological studies have begun to delineate the mechanisms by which HPK1 inhibition can potentiate cytokine release, overcome suppressive microenvironment cues and synergise with checkpoint blockade therapies.

Research from Nature Portfolio

Recent structural and biophysical investigations have illuminated how the non-catalytic CHD engages the kinase domain of HPK1 to regulate its activity. High-resolution crystallography and hydrogen–deuterium exchange mass spectrometry reveal that the CHD adopts a seven-bladed β-propeller fold that docks onto the kinase domain. Mutagenesis studies demonstrate that disruption of this interface destabilises HPK1 in the cellular context and impairs its ability to phosphorylate the adaptor SLP-76. These findings underscore the importance of intramolecular interactions in maintaining HPK1’s autoinhibited conformation and provide a blueprint for allosteric modulation of kinase activity in therapeutic settings.

Hematopoietic Kinase Modulation in T Cell Signaling publication trend

The graph below shows the total number of articles in hematopoietic kinase modulation in t cell signaling across all publications each year (not limited to Nature Index journals).

Technical terms

HPK1: Hematopoietic progenitor kinase 1, a serine/threonine kinase that negatively regulates TCR signalling.

CHD (Citron Homology Domain): A β-propeller structural domain in HPK1 that mediates autoinhibitory interactions with the kinase domain.

TCR (T Cell Receptor): A multi-subunit complex on T cells that recognises antigenic peptides and initiates intracellular signalling cascades.

SLP-76: An adaptor protein phosphorylated by HPK1, critical for the assembly of signalling complexes downstream of the TCR.

Ubiquitination: A post-translational modification involving attachment of ubiquitin to lysine residues, often targeting proteins for degradation or altering their activity.

References

1. Involvement of Hematopoietic Progenitor Kinase 1 in T Cell Receptor Signaling*. Journal of Biological Chemistry (2001).
2. Hematopoietic Progenitor Kinase 1 Associates Physically and Functionally with the Adaptor Proteins B Cell Linker Protein and SLP-76 in Lymphocytes*. Journal of Biological Chemistry (2001).
3. HPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics. Nature Communications (2024).
4. Attenuation of T Cell Receptor Signaling by Serine Phosphorylation-mediated Lysine 30 Ubiquitination of SLP-76 Protein*. Journal of Biological Chemistry (2012).
5. Theoretical Studies on Selectivity of HPK1/JAK1 Inhibitors by Molecular Dynamics Simulations and Free Energy Calculations. International Journal of Molecular Sciences (2023).
6. Critical role of kinase activity of hematopoietic progenitor kinase 1 in anti-tumor immune surveillance. PLOS ONE (2019).
7. Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function. PLOS ONE (2020).