Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility.

The candidate tumor-suppressor gene hyaluronidase 2 (HYAL2) encodes a glycosylphosphatidylinositol-anchored cell-surface protein that serves as an entry receptor for jaagsiekte sheep retrovirus, a virus that causes contagious lung cancer in sheep that is morphologically similar to human bronchioloalveolar carcinoma. The viral envelope (Env) protein alone can transform cultured cells, and we hypothesized that Env could bind and sequester the HYAL2 receptor and thus liberate a potential oncogenic factor bound and negatively controlled by HYAL2. Here we show that the HYAL2 receptor protein is associated with the RON receptor tyrosine kinase (also called MST1R or Stk in the mouse), rendering it functionally silent. In human cells expressing a jaagsiekte sheep retrovirus Env transgene, the Env protein physically associates with HYAL2. RON liberated from the association with HYAL2 becomes functionally active and consequently activates the Akt and mitogen-activated protein kinase pathways leading to oncogenic transformation of immortalized human bronchial epithelial cells. We find activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer.

Section: Resultsmentioning

confidence: 99%

“…It has been reported that a (26). However a common progenitor cell for these cell types, which probably gives rise to BAC, may reside in the bronchiolar compartment and may express RON (26). The heterogeneity of the differentiation phenotype within BAC lesions has been well established.…”

Section: Resultsmentioning

confidence: 99%

Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus

Danilkovitch‐Miagkova

Duh

Kuzmin

et al. 2003

“…MST1R encodes a cell surface receptor for macrophage-stimulating 1 (MST1, also known as MSP) with tyrosine kinase activity. Previous studies show that MST1R plays a critical function in host defense: (i) It is predominantly expressed in the tissue-resident macrophages, which promote tissue repair and inhibit inflammation by repressing the production of proinflammatory molecules induced by pathogens (14)(15)(16)(17) and (ii) MST1R expression is detected in the ciliated epithelial cells in the normal nasal mucosa, and activation of MST1R signaling can increase the ciliary motility to prevent chronic infection (18). Previous studies and our WES data strongly support the role of MST1R as an NPC susceptibility gene.…”

Section: Significancementioning

confidence: 99%

Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma

Dai

Zheng

Cheung

et al. 2016

Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germline variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs.

“…In this regard, we note that although traditionally considered components of blood, both plasminogen and MSP are present in the respiratory tract. Plasminogen is found in saliva and MSP is present in bronchoalveolar lavage fluid (25,26). Additionally the MSP receptor, RON, is highly expressed in the upper respiratory tract where it regulates motility of ciliated epithelia (26).…”

Section: Short-term Changes In the Host Transcriptional Response To Gasmentioning

confidence: 99%

“…Plasminogen is found in saliva and MSP is present in bronchoalveolar lavage fluid (25,26). Additionally the MSP receptor, RON, is highly expressed in the upper respiratory tract where it regulates motility of ciliated epithelia (26). MSP activation of RON suppresses the inflammatory response by inhibiting nitric oxide production in macrophages and may represent a unique mechanism by which GAS evades the host immune response.…”

Section: Short-term Changes In the Host Transcriptional Response To Gasmentioning

confidence: 99%

Interactome analysis of longitudinal pharyngeal infection of cynomolgus macaques by group A Streptococcus

Shea

Virtaneva

Kupko

et al. 2010

Relatively little is understood about the dynamics of global hostpathogen transcriptome changes that occur during bacterial infection of mucosal surfaces. To test the hypothesis that group A Streptococcus (GAS) infection of the oropharynx provokes a distinct host transcriptome response, we performed genome-wide transcriptome analysis using a nonhuman primate model of experimental pharyngitis. We also identified host and pathogen biological processes and individual host and pathogen gene pairs with correlated patterns of expression, suggesting interaction. For this study, 509 host genes and seven biological pathways were differentially expressed throughout the entire 32-day infection cycle. GAS infection produced an initial widespread significant decrease in expression of many host genes, including those involved in cytokine production, vesicle formation, metabolism, and signal transduction. This repression lasted until day 4, at which time a large increase in expression of host genes was observed, including those involved in protein translation, antigen presentation, and GTP-mediated signaling. The interactome analysis identified 73 host and pathogen gene pairs with correlated expression levels. We discovered significant correlations between transcripts of GAS genes involved in hyaluronic capsule production and host endocytic vesicle formation, GAS GTPases and host fibrinolytic genes, and GAS response to interaction with neutrophils. We also identified a strong signal, suggesting interaction between host γδ T cells and genes in the GAS mevalonic acid synthesis pathway responsible for production of isopentenyl-pyrophosphate, a short-chain phospholipid that stimulates these T cells. Taken together, our results are unique in providing a comprehensive understanding of the host-pathogen interactome during mucosal infection by a bacterial pathogen.epithelial growth factor receptor | host pathogen | microarray | Streptococcus pyogenes | transcriptome