Inhibition of MSP-RON signaling pathway in cancer cells by a novel soluble form of RON comprising the entire sema sequence

Abstract

Abstract. The RON receptor tyrosine kinase and its ligand macrophage stimulating protein (MSP) play a role in epithelial tumorigenesis. We report here a novel RON variant that antagonizes the RON-MSP pathway in various cancer cells. The variant is an 85 kDa soluble protein from an mRNA transcript with an insertion of 49 nucleotides between exons 5 and 6. The insertion created a stop codon leading to the formation of a RON variant consisting of the entire 35 kDa ·-chain and a 45 kDa partial extracellular ß-chain. The protein was featured by a sema domain, a hinge motif and a portion of the first IPT unit (designated as RONΔ85). RONΔ85 binds directly to MSP, forms MSP-RONΔ85 complex, and inhibits RON phosphorylation. RONΔ85 disrupts RON or RONΔ160 dimerization, prevents their phosphorylation, and attenuates downstream signaling events. The action of RONΔ85 is specific to RON and has no effect on MET and EGFR. In colon and pancreatic cancer cells, RONΔ85 inhibits spontaneous or MSP-induced Erk1/2 and AKT phosphorylation, which results in impaired cell proliferation and colony formation. RONΔ85 also inhibits spontaneous and MSPinduced cell migration. We conclude that RONΔ85 is an antagonist to the MSP-RON pathway, which has potential for regulating RON/RON160-mediated tumorigenic activities.

Mutated axon guidance gene PLXNB2 sustains growth and invasiveness of stem cells isolated from cancers of unknown primary

“…This amino acid site is topologically conserved in six out of nine members of the human plexin family; moreover, it is located upstream of two cysteines (in +3 and +18 position), which are conserved in the corresponding IPT domain of all plexins, and known to be linked by a disulfide intramolecular bond (Fig 2). A similar structure is found in the homologous first IPT domain of Met and Ron tyrosine kinase receptors, which were previously found to be affected by activating mutations in human cancers (Ma et al , 2010; Navis et al , 2015).…”

“…In order to establish a proof of principle about the relevance of axon guidance genes in CUPs, we investigated G842C-PlxnB2 variant, which was suspected to be damaging based on sequence conservation and structural modeling results. Moreover, this mutation affected the conserved fold of an IPT domain, a moiety also found in Met and Ron oncogenic receptors and previously found to be affected by activating mutations in human cancers (Ma et al, 2010;Navis et al, 2015). Notably, the large intracellular portion of the plexins does not contain a kinase domain or other classical signaling domains, but was consistently reported to regulate the activity of monomeric GTPases, especially R-Ras, Rap-1, and RhoA, controlling cell migration, and axonal extension in neural development.…”

Urine proteome changes in rats subcutaneously inoculated with approximately ten tumor cells

“…In addition, we found that some pathways were reported to play important roles in cancer. For example, (i) autophagy was reported to inhibit tumor progression (Peng et al, 2016); (ii) the MSP-RON signaling pathway was reported to play important roles in epithelial tumorigenesis (Ma et al, 2010) and will facilitate metastasis in prostate cancer cells (Yin et al, 2017); (iii) tissue factor (TF) expressed by tumor cells was reported to facilitate lung tumor progression (Han et al, 2017); (iv) upregulation of the pentose phosphate pathway (PPP) has been reported in several types of cancer (Rao et al, 2015); and (v) the enriched complement system pathway was reported to enhance the metastatic process of ovarian cancer cells (Cho et al, 2016). Our results indicated that even when limited tumor cells are present in the body, the urine proteome can reflect changes associated with cancer.…”

From Biology to Diagnosis and Treatment: The Ariadne’s Thread in Cancer of Unknown Primary

“…The G842C-PlxnB2 variant has been investigated in an effort to establish a proof of principle about the relevance of axon guidance genes in CUP. This mutation affected the conserved fold of an IPT domain, a moiety also found in Met and Ron oncogenic receptors [ 72 , 73 ]. Notably, the large intracellular portion of the plexins does not contain a kinase domain or other classical signalling domains; nevertheless, it regulates the activity of monomeric GTPases, especially R-Ras, Rap-1, and RhoA.…”