MST1R

Official Full Name

macrophage stimulating 1 receptor

Organism

Homo sapiens

GeneID

4486

Background

This gene encodes a cell surface receptor for macrophage-stimulating protein (MSP) with tyrosine kinase activity. The mature form of this protein is a heterodimer of disulfide-linked alpha and beta subunits, generated by proteolytic cleavage of a single-chain precursor. The beta subunit undergoes tyrosine phosphorylation upon stimulation by MSP. This protein is expressed on the ciliated epithelia of the mucociliary transport apparatus of the lung, and together with MSP, thought to be involved in host defense. Alternative splicing generates multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Jan 2016]

Synonyms

RON; SEA; PTK8; CD136; NPCA3; CDw136; p185-Ron;

Bio Chemical Class

Kinase

Protein Sequence

MELLPPLPQSFLLLLLLPAKPAAGEDWQCPRTPYAASRDFDVKYVVPSFSAGGLVQAMVTYEGDRNESAVFVAIRNRLHVLGPDLKSVQSLATGPAGDPGCQTCAACGPGPHGPPGDTDTKVLVLDPALPALVSCGSSLQGRCFLHDLEPQGTAVHLAAPACLFSAHHNRPDDCPDCVASPLGTRVTVVEQGQASYFYVASSLDAAVAASFSPRSVSIRRLKADASGFAPGFVALSVLPKHLVSYSIEYVHSFHTGAFVYFLTVQPASVTDDPSALHTRLARLSATEPELGDYRELVLDCRFAPKRRRRGAPEGGQPYPVLRVAHSAPVGAQLATELSIAEGQEVLFGVFVTGKDGGPGVGPNSVVCAFPIDLLDTLIDEGVERCCESPVHPGLRRGLDFFQSPSFCPNPPGLEALSPNTSCRHFPLLVSSSFSRVDLFNGLLGPVQVTALYVTRLDNVTVAHMGTMDGRILQVELVRSLNYLLYVSNFSLGDSGQPVQRDVSRLGDHLLFASGDQVFQVPIQGPGCRHFLTCGRCLRAWHFMGCGWCGNMCGQQKECPGSWQQDHCPPKLTEFHPHSGPLRGSTRLTLCGSNFYLHPSGLVPEGTHQVTVGQSPCRPLPKDSSKLRPVPRKDFVEEFECELEPLGTQAVGPTNVSLTVTNMPPGKHFRVDGTSVLRGFSFMEPVLIAVQPLFGPRAGGTCLTLEGQSLSVGTSRAVLVNGTECLLARVSEGQLLCATPPGATVASVPLSLQVGGAQVPGSWTFQYREDPVVLSISPNCGYINSHITICGQHLTSAWHLVLSFHDGLRAVESRCERQLPEQQLCRLPEYVVRDPQGWVAGNLSARGDGAAGFTLPGFRFLPPPHPPSANLVPLKPEEHAIKFEYIGLGAVADCVGINVTVGGESCQHEFRGDMVVCPLPPSLQLGQDGAPLQVCVDGECHILGRVVRPGPDGVPQSTLLGILLPLLLLVAALATALVFSYWWRRKQLVLPPNLNDLASLDQTAGATPLPILYSGSDYRSGLALPAIDGLDSTTCVHGASFSDSEDESCVPLLRKESIQLRDLDSALLAEVKDVLIPHERVVTHSDRVIGKGHFGVVYHGEYIDQAQNRIQCAIKSLSRITEMQQVEAFLREGLLMRGLNHPNVLALIGIMLPPEGLPHVLLPYMCHGDLLQFIRSPQRNPTVKDLISFGLQVARGMEYLAEQKFVHRDLAARNCMLDESFTVKVADFGLARDILDREYYSVQQHRHARLPVKWMALESLQTYRFTTKSDVWSFGVLLWELLTRGAPPYRHIDPFDLTHFLAQGRRLPQPEYCPDSLYQVMQQCWEADPAVRPTFRVLVGEVEQIVSALLGDHYVQLPATYMNLGPSTSHEMNVRPEQPQFSPMPGNVRRPRPLSEPPRPT

Open

Disease

Alzheimer disease, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The MST1R gene, also known as RON (Recepteur d'Origine Nantais), is located on chromosome 3p21.31 and spans approximately 50 kb. It contains 20 exons and encodes a 140 kDa type I transmembrane receptor tyrosine kinase (UniProt ID: Q04912). Structurally, the RON protein consists of an extracellular Sema domain responsible for ligand binding, a PSI (plexin-semaphorin-integrin) domain, four IPT domains involved in receptor dimerization and signal transduction, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. Following intracellular cleavage between Arg308 and Ser309, a mature heterodimeric receptor is formed, composed of a 40 kDa α-chain and a 150 kDa β-chain, joined by disulfide bonds. The ligand macrophage-stimulating protein (MSP, also known as HGFL) binds to RON with high affinity (Kd = 0.45 nM), leading to phosphorylation of tyrosine residues Tyr1238 and Tyr1239, and activating the PI3K–Akt–mTOR, RAS–MAPK, and β-catenin pathways. These cascades drive epithelial-mesenchymal transition (EMT), cell migration, and resistance to apoptosis.

Expression and Regulation

In normal tissues, MST1R expression is restricted to epithelial cells of the gastrointestinal tract, kidney, and liver. However, overexpression or aberrant activation is found in numerous tumors, including breast, colorectal, pancreatic, and bladder cancers. Epigenetically, MST1R expression is upregulated through promoter hypomethylation and enhanced H3K4me3 modifications. Furthermore, the alternative splicing variant ΔRON, which lacks exon 11 and encodes a constitutively active form, is frequently detected in invasive breast cancer (64%) and correlates with enhanced motility and metastatic potential. Notably, ΔRON is resistant to ligand dependency and exhibits prolonged half-life due to impaired degradation.

Targeted Therapies and Resistance

Several therapeutic strategies are under investigation:

Small Molecule Inhibitors: BMS-777607 is a selective MST1R/Met dual inhibitor (IC₅₀ = 1.8 nM for RON), currently in clinical trials for gastric and pancreatic cancers. Treatment reduces phosphorylated STAT3 levels by 72% in responsive models.
Monoclonal Antibodies: Narnatumab, a humanized IgG1 antibody, blocks MSP binding and induces antibody-dependent cellular cytotoxicity (ADCC). However, limited single-agent efficacy prompted exploration in combination therapies.
Antisense Oligonucleotides (ASOs): In mouse xenograft models, ASOs targeting MST1R mRNA suppressed tumor growth by 48% and reversed EMT markers (increase in E-cadherin, decrease in Snail and Twist1).

Therapeutic resistance is often associated with compensatory activation of MET or EGFR, or the emergence of exon-skipping variants that lack the antibody-binding epitope.

A Nucleolar Multitasker in Oncogenesis

Molecular Characteristics: The NCL gene is located on chromosome 2q37.1 and spans approximately 12.5 kb. It encodes nucleolin, a multifunctional protein of 707 amino acids with a molecular weight of ~77 kDa (UniProt ID: P19338). Nucleolin contains an N-terminal domain rich in acidic residues, four RNA recognition motifs (RRMs), and a C-terminal domain rich in arginine and glycine repeats (RGG domain), which mediates interactions with RNA and DNA. It is predominantly localized in the nucleolus but also shuttles to the cytoplasm and cell membrane. Post-translational modifications, including phosphorylation (by CK2 and PKC), methylation, and acetylation, regulate its localization and activity.

Function and Expression: Nucleolin is essential for ribosomal RNA transcription, pre-rRNA processing, and ribosome assembly. In addition, it modulates mRNA stability, chromatin remodeling, and signal transduction. Aberrant nucleolin expression is observed in a wide range of tumors, including glioblastoma, leukemia, and hepatocellular carcinoma. It correlates with tumor grade, proliferation index (Ki-67), and poor prognosis. Importantly, nucleolin can translocate to the plasma membrane in cancer cells, where it acts as a receptor or co-receptor for various ligands (e.g., midkine, P-selectin) and facilitates cell adhesion and invasion.

Figure 1. Model demonstrating the role of RON as a transcription factor that promotes cell survival during cellular stress. (Cazes A, et al., 2022)

Targeted Approaches and Mechanistic Insights

Nucleolin-Targeted Aptamers: AS1411 is a G-rich DNA aptamer that binds to surface-expressed nucleolin with nanomolar affinity, leading to G1-phase arrest and apoptosis. In phase II trials for renal and AML patients, AS1411 showed acceptable safety and modest efficacy.
Immunotoxins and Conjugates: NCL-targeted immunotoxins (e.g., NCL-saporin) and gold nanoparticle conjugates have been shown to induce selective tumor cell death with minimal toxicity to normal cells. NCL also enhances IRES-mediated translation of anti-apoptotic proteins like Bcl-2 and XIAP under stress conditions.
RNA-Binding Inhibition: Small molecules that disrupt NCL-G-quadruplex or NCL–oncogenic mRNA complexes are in development, aiming to inhibit pro-survival and angiogenic signaling.

Resistance Mechanisms

Therapeutic resistance may involve compensatory stabilization of oncogenic transcripts by other RBPs (e.g., HuR) or alternative splicing that alters the accessibility of NCL's RRM domains. Furthermore, tumor cells may reduce surface expression of nucleolin, limiting aptamer efficacy.

References:

Cazes A, Childers BG, Esparza E, et al. The MST1R/RON Tyrosine Kinase in Cancer: Oncogenic Functions and Therapeutic Strategies. Cancers (Basel). 2022 Apr 18;14(8):2037.
Hunt BG, Fox LH, Davis JC, et al. An Introduction and Overview of RON Receptor Tyrosine Kinase Signaling. Genes (Basel). 2023 Feb 17;14(2):517.

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