MST1R - macrophage stimulating 1 receptor | Elisa - Clia - Antibody - Protein

Background

MST1R, also known as RON receptor tyrosine kinase or Macrophage-Stimulating 1 Receptor, is a member of the MET proto-oncogene family. This receptor belongs to the receptor tyrosine kinase (RTK) family and plays a crucial role in various physiological processes, particularly those involving inflammation, tissue repair, cell survival, and migration. MST1R is primarily expressed in macrophages, epithelial cells, and some immune cell types and mediates its effects through interaction with its ligand, Macrophage-Stimulating Protein (MSP). Ligand binding to MST1R activates intracellular signaling cascades, leading to cell proliferation, survival, and migration, thus influencing immune responses, tissue repair, and inflammatory responses.

Research has identified the significance of MST1R in the pathology of various diseases, including cancer and fibrotic disorders, due to its ability to promote cellular processes often dysregulated in malignancy and tissue scarring. In cancer, for example, MST1R is often overexpressed or mutated, leading to enhanced tumor progression, metastasis, and treatment resistance. Consequently, MST1R has emerged as a target of interest in the development of anti-cancer therapeutics.

Protein Structure

The structure of MST1R (RON receptor) is complex and consists of three main domains: extracellular, transmembrane, and intracellular regions. These domains work cohesively to enable ligand binding, receptor dimerization, and intracellular signal transduction:

Extracellular Domain:

• MST1R has a large extracellular domain composed of three main subdomains: the Sema (semaphorin) domain, the Plexin-Semaphorin-Integrin (PSI) domain, and immunoglobulin-like (Ig-like) domains. The Sema domain is responsible for ligand binding and is similar to the domain structure seen in other members of the MET family.
• The extracellular domain also contains disulfide bonds and glycosylation sites that contribute to proper protein folding, stability, and receptor-ligand interaction.
• Binding of the MSP ligand to the extracellular domain induces dimerization of MST1R, which is essential for activating its tyrosine kinase activity.

Transmembrane Domain:

• The transmembrane domain anchors the receptor in the plasma membrane. It plays a role in maintaining receptor stability and orientation for effective ligand binding and signal transmission to the intracellular domain.

Intracellular (Cytoplasmic) Domain:

• The intracellular domain of MST1R comprises a split tyrosine kinase domain divided into two lobes (N-lobe and C-lobe). This split structure is characteristic of the MET RTK family and allows for effective control over the kinase activity.
• When the receptor dimerizes in response to MSP binding, autophosphorylation of specific tyrosine residues within the kinase domain occurs. This phosphorylation activates the kinase domain and enables binding of adaptor proteins that initiate downstream signaling pathways.
• Critical autophosphorylation sites within the kinase domain are responsible for recruiting signaling proteins that activate pathways such as PI3K-Akt, MAPK, and JAK-STAT, which collectively contribute to cellular survival, growth, and migration.

Classification and Subtypes

MST1R is classified within the MET proto-oncogene family and is a type I receptor tyrosine kinase (RTK). This receptor class includes MET and its homologs, sharing structural and functional similarities. MST1R is also known as a “hepatocyte growth factor (HGF) receptor family member”, given its structural and functional similarity to MET, the receptor for HGF.

There are two notable isoforms of MST1R:

1. Full-Length MST1R: This is the fully functional form of the receptor, responsible for the primary signaling capabilities upon ligand binding.
2. ΔRON (Splice Variant): A shorter, constitutively active isoform arising from alternative splicing of the MST1R mRNA. ΔRON lacks part of the extracellular domain and is associated with higher oncogenic potential in several cancers, including breast, colon, and pancreatic cancer.

Function and Biological Significance

MST1R functions primarily in mediating macrophage responses, epithelial repair, and immune responses. It achieves this by facilitating key cellular processes, including cell migration, proliferation, and survival. Its main biological functions include:

Regulation of Inflammatory and Immune Responses:

• MST1R expression on macrophages modulates the immune response, helping resolve inflammation. When bound by MSP, MST1R promotes the “anti-inflammatory” M2 macrophage phenotype, which supports tissue repair and resolves inflammation.
• This receptor's activation leads to decreased production of pro-inflammatory cytokines, contributing to an immunosuppressive environment, which, although beneficial in wound healing, can also facilitate tumor evasion of the immune system.

Tissue Repair and Regeneration:

• In epithelial tissues, MST1R signaling contributes to cell proliferation and migration, processes critical in wound healing. Activated MST1R stimulates epithelial cells to migrate to the wound site, proliferate, and participate in tissue remodeling.

Cell Survival and Migration in Oncogenesis:

• MST1R activation is associated with enhanced cellular survival, migration, and invasion in several cancers, contributing to tumor progression and metastasis.
• The signaling pathways activated by MST1R, including PI3K-Akt, MAPK, and JAK-STAT, promote cellular processes commonly dysregulated in cancer, such as growth, apoptosis resistance, and metastatic behavior.

Clinical Issues

Abnormal MST1R expression or function is linked to a range of clinical conditions, particularly cancers and fibrotic diseases. Key clinical issues associated with MST1R include:

Oncogenesis:

• MST1R is often overexpressed or aberrantly activated in several types of cancer, including breast, lung, pancreatic, and colorectal cancer. Its overactivation leads to increased cell proliferation, migration, and survival, all of which are hallmarks of cancer progression.
• The ΔRON splice variant is particularly implicated in aggressive cancer phenotypes. This variant lacks regulatory domains, making it constitutively active, thus continuously driving cancer-promoting signaling pathways.
• The oncogenic role of MST1R has made it a target for cancer therapeutics. Several inhibitors targeting MST1R’s kinase domain are being investigated for their efficacy in blocking cancer progression, and anti-MST1R antibodies are also under exploration for targeted cancer therapy.

Drug Resistance:

• MST1R overactivation has been linked to resistance to chemotherapy in certain cancers. For example, in pancreatic cancer, elevated MST1R signaling is associated with resistance to standard treatments, leading to poor clinical outcomes.
• Targeting MST1R with specific inhibitors may potentially enhance chemotherapy sensitivity, making MST1R a promising candidate for combination therapies to improve patient outcomes.

Fibrosis:

• MST1R’s role in tissue repair and inflammation has implications for fibrotic disorders. Overactivation of MST1R in tissue repair pathways can lead to excessive fibroblast activity and extracellular matrix deposition, contributing to fibrosis in organs such as the liver and lungs.
• Given its involvement in inflammation and tissue remodeling, MST1R is considered a potential therapeutic target in fibrotic diseases, with inhibitors under development aimed at controlling the fibrotic response by modulating MST1R activity.

Summary

MST1R (RON receptor tyrosine kinase) is a critical regulator of cellular functions related to macrophage activity, tissue repair, and inflammation. As a type I RTK of the MET proto-oncogene family, MST1R has a complex structure with extracellular, transmembrane, and intracellular kinase domains. Ligand binding by MSP induces receptor dimerization and subsequent activation, leading to the autophosphorylation of tyrosine residues within the kinase domain, triggering downstream signaling pathways. These pathways—PI3K-Akt, MAPK, and JAK-STAT—promote cell migration, proliferation, and survival, playing essential roles in immune responses and wound healing.

MST1R’s dysregulation is implicated in various diseases, notably cancer and fibrosis. Overexpression or constitutive activation of MST1R, particularly the ΔRON isoform, is associated with aggressive tumor phenotypes and resistance to treatment. These findings highlight MST1R as a promising target for therapeutic intervention in oncology and fibrotic conditions. As research progresses, MST1R inhibitors and monoclonal antibodies targeting this receptor are being investigated for their potential to modulate its activity and improve clinical outcomes in MST1R-associated diseases.