Rabbit Anti-Human MST1R (Phospho Tyr1238/1239) Polyclonal antibody

Background: Aberrant expression of RON, a MET family receptor tyrosine kinase, has been correlated to tumor growth and metastasis. Intense research efforts are on to target RON using small molecule tyrosine kinase inhibitors or specific antibodies. However, progress towards specific targeting of RON is hampered by a lack of understanding of the nature and number of isoforms of RON expressed by tumors. We hypothesize that formation of different isoforms via alternative splicing may be fundamental to the tumor promoting functions associated with aberrantly expressed RON in cancers. Methods: In this study, we analyzed the transcript sequence variations caused by alternative splicing in the C-terminal region of RON cDNA by PCR amplification and sequencing of five small cell lung carcinoma (SCLC) and seven non-small cell lung carcinoma (NSCLC) cell lines. Results: Results revealed the presence of two alternatively spliced variants, each caused by unique exon(s) deletion: a previously known transcript variant lacking exon 19 and a novel one lacking exons 18+19. The two alternatively spliced variants together with the wild-type transcript were detected in each of the 12 lung cancer cell lines analyzed. Combined loss of exons 18+ 19 results in an in-frame deletion of 303 nucleotides corresponding to 101 amino acids of the tyrosine kinase domain. Translation products of transcript variants lacking exons 18 and 19 are expected to dominant negatively inhibit ligand stimulated RON signaling. Conclusions: The ubiquitous presence of alternatively spliced transcripts and their translation products may affect quantitative expression analysis, either by immunological or PCR methods, by interfering with estimation of normal RON, leading to exaggerated values. Besides, RON isoforms with dominant negative activities may interfere with siRNA based functional analysis of wild-type RON.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest epithelial malignancies and remains difficult to treat. Pancreatic intraepithelial neoplasias (PanlNs) represent the majority of the pre-cancer lesions in the pancreas. The PDAC microenvironment consists of activated pancreatic stellate cells (PSCs) and immune cells, which are thought to contribute to neoplastic transformation. However, the signaling events involved in driving the transition from the neoplastic precursor to the more advanced and aggressive forms in the pancreas are not well understood. Recepteur d'Origine Nantais (RON) is a c-MET family receptor tyrosine kinase that is implicated in playing a role in cell proliferation, migration and other aspects of tumorigenesis. Macrophage stimulating protein (MSP) is the ligand for RON and becomes activated upon proteolytic cleavage by matriptase (also known as ST14), a type II transmembrane serine protease. In the current study, by immunohistochemistry (IHC) analysis of human pancreatic tissues, we found that the expression levels MSP and matriptase are drastically increased during the transition from the preneoplastic PanIN stages to the more advanced and aggressive PDAC. Moreover, RON is highly expressed in both PDAC and in cancer-associated stellate cells. In contrast, MSP, RON, and matriptase are expressed at low levels, if any, in normal pancreas. Our study underscores an emerging role of MSP-RON autocrine and paracrine signaling events in driving malignant progression in the pancreas.