Serine Protease Signaling in Cancer Biology

Serine proteases form a versatile class of enzymes that orchestrate numerous processes within tumour initiation, progression and metastasis. These proteolytic factors operate via a catalytic serine residue to cleave specific peptide bonds, thereby modulating the extracellular environment, activating latent growth factors and influencing cell–cell communication. Within the tumour microenvironment, membrane-anchored serine proteases such as matriptase, prostasin and hepsin regulate pericellular proteolysis, liberating pro-growth signals including hepatocyte growth factor and TGFβ. Concurrently, serine proteases engage protease-activated receptors on tumour and stromal cells, initiating downstream signalling cascades that drive proliferation, migration and inflammatory responses. Crosstalk between serine proteases and protease inhibitors establishes finely tuned proteolytic cascades essential for epithelial barrier function, angiogenesis and immune evasion. Aberrant expression or activation of these enzymes disrupts homeostatic proteolytic control, contributing to enhanced invasiveness, extracellular matrix remodelling and metastatic dissemination. Exploiting the interconnections between coagulation, fibrinolysis and classical growth factor pathways, recent work emphasises the multifaceted roles of serine protease networks in shaping tumour biology and identifies promising avenues for therapeutic intervention through selective inhibition of protease activity or zymogen activation.

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Serine Protease Signaling in Cancer Biology publication trend

The graph below shows the total number of articles in serine protease signaling in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Zymogen: An inactive precursor enzyme that requires proteolytic cleavage for activation.

Proteolytic cascade: A sequential activation process in which one protease cleaves and activates another, amplifying the proteolytic signal.

Type II transmembrane serine protease: A membrane-anchored protease with an extracellular catalytic domain and a single transmembrane helix.

Exosome: A small extracellular vesicle released by cells that mediates intercellular transfer of proteins and nucleic acids.

Protease-activated receptor (PAR): A cell-surface receptor activated by proteolytic cleavage of its extracellular domain, triggering intracellular signalling.

References

1. Intersection of Coagulation and Fibrinolysis by the Glycosylphosphatidylinositol (GPI)-Anchored Serine Protease Testisin. International Journal of Molecular Sciences (2023).
2. Exosome-Mediated Activation of the Prostasin-Matriptase Serine Protease Cascade in B Lymphoma Cells. Cancers (2023).
3. Hepsin promotes breast tumor growth signaling via the TGFβ‐EGFR axis. Molecular Oncology (2023).