The macrophage-stimulating protein receptor (MST1R), also known as PTK8, RON, or CD136, is a receptor tyrosine kinase that transduces extracellular matrix signals into the cytoplasm, exerting its function by binding to the MST1 ligand. RON can homodimerize via ligand binding, heterodimerize with other tyrosine kinases, and constitutively activate as an alternative isoform or splice variant. Activation then regulates various physiological processes, including cell survival, migration, and differentiation.
(Data source: Cazes A, et al. Cancers (Basel). 2022)
MST1R expression distribution
MST1R is mainly expressed in gastric mucus-secreting cells, distal intestinal epithelial cells, intestinal goblet cells, type I alveolar cells, and proximal intestinal epithelial cells.
(Data source: unprot)
Structure and ligands of MST1R
MSTIR is a single-pass type I transmembrane protein composed of 1400 amino acids with a molecular weight of approximately 180 kDa. RON initially exists as an inactive precursor, pro-RON, which requires hydrolysis to become the active form. RON consists of a 35-kDa α chain and a 145-kDa β chain. Furthermore, the α chain contains an N-terminus of the SEMA domain, while the β chain contains a C-terminus of the SEMA domain, a PSI motif, four IPT domains, a transmembrane region, an intracellular kinase domain, and a C-terminal tail.
Like RON, MSP initially exists as an inactive precursor, pro-MSP. Mature MSP is produced through protein hydrolysis, which produces α/β heterodimers linked by disulfide bonds. This process is crucial for its biological function.
MSP contains two structurally distinct receptor-binding domains. The β chain of MSP contains a high-affinity binding site that specifically interacts with the SEMA domain of RON. The low-affinity site in the α chain of MSP binds to RON, and this sequential binding triggers a conformational rearrangement of the RON β chain, leading to autophosphorylation of Tyr1238 and Tyr1239 in the intracellular kinase domain.
(Data source: Wu K, et al. Cell Commun Signal. 2025)
MST1R signaling pathway and regulation
The binding of the ligand MSP to the extracellular domain of RON induces receptor dimerization and trans-autophosphorylation of specific tyrosine residues in the intracellular kinase domain, thereby activating downstream signaling pathways. The MAPK/ERK pathway regulates cell proliferation and survival. The PI3K/AKT pathway promotes cell survival and metabolic regulation. The JAK/STAT pathway participates in immune regulation and inflammatory responses.
(Data source) Wu K, et al. Cell Commun Signal. 2025)
RON activation in the tumor microenvironment triggers changes in cancer-associated fibroblasts, T cells, and tumor-associated macrophages, ultimately creating an environment that allows tumor growth. In B cancer cells, RON activation leads to increased proliferation, activation of survival pathways, enhanced stress tolerance, and upregulation of epithelial-mesenchymal transition (EMT)-related genes.
(Data source: Cazes A, et al. Cancers (Basel). 2022)
MST1R targeted therapy
Narnatumab is a monoclonal antibody targeting MST1R. It binds to RON, prevents MSP binding, and blocks MSP-RON signaling. Its highest development stage is Phase 1 clinical trials. It is characterized by good tolerability but limited antitumor activity. No recent research progress has been found.
Ztg4-MMAE is a targeted antibody-drug conjugate that achieved complete tumor clearance in a xenograft model with RON overexpression, thus expanding the application prospects of RON targeted therapy strategies through precise drug delivery technology.
(Data source: Wu K, et al. Cell Commun Signal. 2025)
