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Introduction
Receptor tyrosine kinases (RTK) are transmembrane proteins with unique structural
properties[1,2]. Currently, twenty families of RTK have been
identified[2]. They all share a similar structure consisting of a large extracellular domain, a short
transmembrane segment, and an intracellular component with intrinsic tyrosine kinase
activity[1,2]. The typical examples of
RTK are EGFR and MET[3,4]. Upon binding of a specific ligand, the corresponding RTK undergoes dimeriza-tion, resulting in
autophosphorylation of tyrosine residues in various domains that activate the intrinsic tyrosine kinase
activities[5]. By recruiting, interacting with, and catalyzing various intracellular signaling proteins, the activated RTK gives rise to multiple
signaling cascades that lead to gene activation and biological
responses[5,6]. The activation of RTK can also be achieved
through ligand-independent
mechanisms[1]. Mutation, deletion, truncation, chromosomal rearrangement, and translocation
have been widely documented in abnormal RTK activation under various pathological
conditions[1]. In certain human tumors, aberrant RTK expression and activation, such as increased expression of the EGFR family members in breast and lung
cancers, are hallmarks of tumor
progression[7]. Thus, RTK are potential targets for therapeutic intervention. The inhibition
of RTK activities by specific inhibitors, such as Herceptin which blocks EGFR2 (Her2), significantly improves clinical
outcomes in patients with breast or lung
cancer[8].
The recepteur dĄŻorigine nantais (RON) receptor tyrosine kinase belongs to the MET proto-oncogene
family[9]. Since its discovery in
1993[9], significant progress has been made to elucidate its biochemical and biological
properties[10,11]. RON has been found to be essential in embryonic development and in tumor invasive/malignant
phenotypes[10,12]. This review summarizes current knowledge of RON in cancer progression and its potential as a therapeutic target. It is believed that by
determining the mechanisms of RON in cancer pathogenesis we should not only be able to understand the pathogenic roles
of RTK in epithelial cancer progression, but also have valuable information about novel strategies to treat malignant cancers.
Biochemical properties of RON and macro-phage stimulating protein(MSP)
RON gene and protein Human RON cDNA was cloned in 1993 from a keratinocyte cDNA
library[9]. It encodes a protein with characteristics of a receptor tyrosine
kinase[9]. The RON gene contains 20 exons and 19 introns and resides on
chromosome 3p21[13,14]. The murine homologue of RON, known as stem cell derived kinase(STK) , was isolated from bone
marrow cells[15]. The RON cDNA encodes 1400 amino acids, which is synthesized first as a single-chain precursor
(pro-RON)[9]. Maturation occurs in the cell membrane resulting in a 180-kDa heterodimeric protein composed of a 40 kDa
a-chain and a 150 kDa transmembrane b-chain with intrinsic tyrosine kinase
activity[16,17]. The extracellular sequences of RON contain
several domains that include an
N-terminal semaphoring (sema) domain, followed by the plexin, semaphor-, and integrin (PSI) domain, and four
immunoglobulin-like IPT domains[9]. RON gene transcripts are present in the liver, lung, brain, kidney, bone, adrenal glands, testis, and
digestive tract[18]. Western and Northern blot analyses indicate that RON is primarily expressed in cells of epithelial origin
such as colon, breast, and skin[9,18]. Fibroblasts do not express RON. Promoter analysis of the RON gene transcription
showed that SP-1 sites are important for RON gene transcription in epithelial
cells[19]. The turnover of the RON protein is
regulated through a mechanism in which c-Cbl ubiquitin ligase binds to phosphorylated RON, leading to its endocytosis and
subsequent degradation[20].
Develop-mentally, RON is required for normal embryogenesis. Complete disruption of the RON gene (knockout) leads to the
death of mouse embryos in the early
stages[12].
Structurally, RON is a member of the MET proto-oncogene
family[21], a distinct subfamily of
RTK[1]. Only two members of the MET family, MET and RON, exist as is evident from human genomic sequence
analysis[22]. MET is the receptor for hepatocyte growth factor/scatter
factor[23] and has a well-described role in tumor
progression[3]. Proteins highly homologous
to human RON have been identified in other species including
mouse[15,24], chicken[25,26],
xenopus[27], and puffer
fish[28]. In avian erythroblastosis retrovirus S13 that causes sarcoma, erythroblastosis, and anemia in young
chicks[29], an oncoprotein called V-Sea was identified in the viral
genome[30]. V-Sea is a hybrid protein containing the chicken Sea kinase domain fused
with viral envelope sequences[31,32]. These data suggest that RON is evolu-tionally conserved in different species.
MSP gene and protein The only ligand identified for RON is
MSP[16,17], a serum-derived protein that belongs to the
plasminogen-related growth factor
family[33,34]. MSP was discovered during the study of macrophage spreading, migration,
and phagocytosis[33]. Sequence analysis confirmed that MSP is an 80 kDa protein with a putative signal peptide followed by
a pre-activation segment, four kringle domains, and a serine-protease-like domain with the substitution of three amino acids
in the active sites[34]. Between the 4th kringle domain region and the serine-protease like domain is an amino acid sequence
(Arg483-Val-Val-gly-gly) serving as the cleavage
site[34]. Thus, MSP is synthesized first as a single-chain precursor
(pro-MSP). The proteolytic cleavage of pro-MSP yields a two-chain
(a/b) mature MSP. Receptor binding and crystal structural
analyses proved that MSP b-chain binds to RON in an `enzyme-substrateĄŻ
mode[35,36].
MSP is evolutionally conserved in different species. The cDNAs encoding human, mouse, chicken, and xenopus MSP
have been isolated[26,27,34,37]. Among various tissues examined, MSP mRNA expression is mainly detected in
hepatocytes[33,34,38], suggesting that liver cells are the major sources of MSP. Recent studies have shown that MSP mRNA is also present in
cells from the kidney and lung[39,40]. However, the significance of these findings remains to be determined.
MSP is constantly produced and circulated in blood at
optimal concentration as a biologically inactive
pro-MSP[41,42]. The amount of pro-MSP in serum is approximately 2 to 5
nmol/L[41], a concentration optimal for biological activities. Gene
knockout studies have revealed that inactivation of the MSP gene in mice is not
lethal[43]. Mice developed normally and had
no visible phenotypic changes[43]. These results suggest that MSP is not required for embryonic development and growth.
Oncogenic potentials in human epithelial cancers
Altered RON expression in primary human cancers
Systematic analysis of RON expression in normal tissues and
cancer samples has not been studied, although immunohistochemical staining has been conducted in several types of
cancers[44_48]. A significant variation by using different antibodies exists in interpretation of the obtained results. In general,
RON is detectable in certain types of normal cells such as epithelial cells and tissue macrophages. Elevated RON expression
has been found in breast, colon, lung, bladder, and ovarian
cancers[44_48]. The incidence of overexpression ranged from 32.8%
to 59% dependent on individual types of cancers. In breast tissues, RON is relatively low in normal cells and benign lesions
(adenoma and papillomas), but highly expressed in 47% (35 out of 75 cases) of tumor specimens with different histotypic
variants[44]. Increased RON expression was strongly correlated to phosphorylation status and invasive
activity[44], suggesting that RON abnormality plays a role in the progression of human breast carcinomas to invasive-metastatic phenotypes.
Moreover, RON overexpression was an independent predictor of distant relapse in breast
cancer[46].
Another example of abnormal RON expression is in colorectal cancers. RON is moderately expressed in normal colorectal
mucosa, but increased significantly in the majority of primary human colorectal adenocarcinoma samples (29 out of 49
cases)[45]. Accumulated RON is also constitutively active with
autophosphorylation[45,49] as a result of high levels of RON protein
accumulation[45]. These results indicate that the activated RON transduces signals that regulate tumorigenic activities of
colon cancer cells.
Recently, altered RON expression has been found in bladder and ovarian
carcinomas[47,48]. In bladder cancer samples,
aberrant RON expression was positively associated with histological grade, large size, non-papillary contour, and tumor
stage[47]. In primary human ovarian carcinoma
samples[48], the majority (29 out of 53 cases) had increased RON expression
with a mixture of cytoplasmic and membrane staining pattern. Interestingly, the abnormal accumulation of RON is often
accompanied by overexpression of MET in ovarian cancer cells, indicating that co-expression of RON and MET confer a
selective advantage to ovarian cancers cells and might promote tumor
progression[48].
We have recently evaluated the status of RON in various normal tissues and primary cancer samples using tissue
microarray using a highly specific monoclonal antibody (clone
ID2)[50]. Standardized analysis of the obtained results
indicates that RON is wildly expressed in various types of normal cells at various degrees. Significant changes of RON
expression were observed in cancer samples derived from stomach, colon, lung, liver, breast, thyroid, kidney, skin, cervical, bladder,
brain, and lymph nodes (unpublished data). These results provide valuable information about the expression levels of RON
in different types of normal and tumor tissues with significant pathological implications. They also indicate that altered RON
expression is a distinct feature in certain types of cancers that might have prognostic or diagnostic value.
Generation of RON variants and their
activities Altered RON expression in cancer cells is often accompanied by the
generation of RON variants through mRNA splicing, alternative initiation, and protein
truncation[45,49,51], which is responsible
for RON protein diversity. Currently, six RON variants have been
obtained and designated as ROND170, 165, 160, 155,
110, and 55 based on calculated molecular mass (Table 1). Following are the general features of these variants.
1) ROND170 is a variant with a deletion of 46 amino acids coded by exon 19 in the kinase
domain[52]. The deletion also results in a reading-frame shift and creates a new stop code causing additional amino acid deletion. Preliminary results
suggest that this protein is biologically inactive but acts as a dominant negative inhibitor (unpublished data).
2) ROND165 (also known as D-RON) was found in normal and malignant colon and breast tissues
samples[45,53,54]. It has an in-frame deletion of 49 amino acids coded by exon 11 in the extracellular domain of the RON
b-chain. The deletion prevents the proteolytic conversion of
pro-ROND165 into the two-chain form and causes the protein to be retained in the cytoplasm.
ROND165 does not have cell-transforming activities but is capable of inducing cell motile activities in transfected
cells[45,53,54].
3) ROND160 was identified in primary CRC
samples[45,51]. It has an in-frame deletion of 109 amino acids in the extracellular
domain of the b-chain. These 109 amino acids are encoded by exons 5 and
6[13]. Unlike ROND165, the deletion of 109 amino
acids does not affect the proteolytic processing of
pro-ROND160. ROND160 is an oncogenic agent with constitutive kinase
activities resulted from unbalanced numbers of cysteine residues in the extracellular domain of the RON
b-chain[45,51].
4) ROND155 was cloned from two primary CRC
samples[45]. It has a deletion of 158 amino acids coded by exons 5, 6, and 11
in the extracellular domain of the b-chain. ROND155 is constitutively active and capable of inducing tumor formation
in vivo[45].
5) ROND110 is a truncated receptor discovered in certain colon cancer cell
lines[49]. The protein is generated by
proteolytic cleavage at
Arg631-Lys632 residues. Thus,
ROND110 is a variant lacking the RON-a chain and the most extracellu
lar domain of the b-chain. We have recently constructed the
ROND110 cDNA by molecular techniques and the function of
ROND110 is currently under investigation (unpublished data).
6) The last variant is ROND55[55], also known as short form RON. The protein is produced by alternative initiation at
Met913. It contains a short extracellular segment but retains the complete intracellular kinase domain and C-terminal tail.
Studies from mice have indicated that ROND55 is critical in friend leukemia virus-induced erythroid proliferation and
malignancy[56]. In human breast cancer cells,
ROND55 modulate E-cadherin expression and thus might contribute to tumor
progression[57]. Our studies have found that
ROND55 does not have cell transforming activities but is capable of regulating
cellular phenotypes (unpublished data). Thus, the
roles of ROND55 in epithelial cancer pathogenesis remain to be determined.
It is currently unknown how RON variants are generated. DNA analysis indicates that all RON variants are not produced
by abnormalities in the genomic
sequences[45,49,51,53]. However, a recent study showed that skipping of
exons such as exon 11 in ROND65 is controlled by a silencer and an enhancer of splicing located on exon
12[58]. Splicing factor SF2/ASF is responsible for the
generation of ROND165 leading to increased invasive
phenotypes[58]. Thus, splicing RON variants are
generated through a complex mechanism that is critical to post-transcriptional regulation of RON expression and activation.
Tumorigenic activities of RON and its variants
Wild-type (wt) RON has no cellular-transforming activities when
expressed in NIH3T3 cells[59]. However, recent work showed that wtRON has the ability to mediate colony formation by
immortalized human colonic AA/C1 epithelial
cells[60]. The tumorigenic potentials of RON were also demonstrated by
mutational studies[61]. Point mutations in the kinase domain such as D1232H/V or M1254T give RON the ability to cause cell
transformation, tumor growth, and metastasis in nude
mice[61_63]. Molecular modeling revealed that D1232H or M1254T
substitution yieldes a dramatic increase in catalytic efficiency with oncogenic
potential[62,63], suggesting that the single
amino acid substitution favors the transition of the kinase from the inactive to the active state.
The oncogenic activities of two RON variants,
ROND160 and ROND155 provide additional evidence indicating that RON
is tumorigenic when its expression is
altered[45]. Subcutaneous inoculation of NIH3T3 cells expressing
ROND160 produced tumors in athymic nude mice and caused tumor metastasis to the
lung[45]. Similarly, cells expressing
ROND155 mediated tumor growth even though its efficiency is relatively
low[45]. To our knowledge, these are the first naturally occurring RON variants
identified to have tumor-producing activity.
A transgenic mouse model has also provided evidence indicating that RON overexpression can lead to tumor formation
in vivo[64]. Overexpression of human RON in distal lung epithelial cells resulted in the formation of multiple lung adenomas
and adenocarcinomas with unique cell morphology and growth
pattern[64,65]. Tumors residing in peripheral portions of the
lung appeared as solid-alveolar adenomas/adenocarcinomas and progressed slowly. Significant cellular atypia with a high
mitotic index was observed in tumors at later stages. Some tumors showed distinct features of bronchioloalveolar carcinoma
or large cell undifferentiated carcinoma with the pallor of the cytoplasm present in the tumors as well as the tremendous
pleomorphism of cellular size and nuclear
morphology[66]. Increased RON expression also led to genomic instability in tumor
samples[64], suggesting that overexpression is the driving force leading to tumor initiation and progression in the lung distal
epithelial cells in vivo.
RON-mediated invasive phenotypes RON-mediated cell motility including cell spreading, dissociation, migration, and
matrix invasion are important functions essential for epithelial cell development and
homeostasis[67]. These activities are also
the hallmark of malignancy that distinguishes cancerous cells from benign tumors. Thus far, RON has been found to induce
cell spreading, dissociation, migration, matrix invasion, and tubular formation in a variety of transformed or cancerous cells.
Studies in vivo have further demonstrated that altered RON expression increases the metastatic potentials of
tumors[61,62]. As shown in experimental lung metastasis experiments, NIH3T3 cells expressing RON mutants, such as M1254T or D1232V,
display increased lung colonization
activity[61]. Similarly, cells harboring splicing RON variants
ROND160 or ROND150 have shown enhanced metastatic activities in athymic nude
mice[45]. These results provide convincing evidence suggesting that
RON-mediated invasive growth is manifested not only in cell culture but also in living animals.
Increased cellular invasiveness is often observed in a complicated event called epithelial-mesenchymal transition
(EMT)[67,68], a distinct feature occurring during embryonic development and in tumor progression towards metastasis. RON has the
ability to act independently or cooperate with other growth factors to induce
EMT[69]. EMT is characterized by the loss of
epithelial properties and the acquisition of mesenchymal
phenotypes[67,68]. The typical EMT consists of the acquisition of a
spindle-shaped morphology, delocalization of E-cadherin from cell junctions, elevated N-cadherin transcription, and
expression of mesenchymal cellular markers such as
b-smooth muscle actin[67,68]. Certain growth factors such as
TGF-b or HGF/SF are known to induce EMT.
Using kidney epithelial cells as a model, we found that RON expression causes MDCK cell scattering with clear
spindle-shaped morphology[69]. Cells also migrated through the collagen reconstituted basement membrane and penetrated into the
Matrigel after MSP stimulation. Moreover, RON activation results in the redistribution of E-cadherin and re-expression of
N-cadherin in spindle-shaped MDCK cells. These data suggest that RON activation directs a biochemical program that is
indistinguishable from TGF-b1 or other growth factor-induced EMT.
Additional studies further demonstrated that RON activation resultes in increased expression of the Smad 2 protein and directly causes its
phosphorylation[69]. Smad 2 is a signal molecule
responsible for TGF-b-induced biological activities including
EMT[70]. The fact that RON activation mediates
Smad 2 expression and phosphorylation suggests that RON-mediated EMT in epithelial cells might be channeled through the
TGF-b/Smad signaling pathway. In support of this notion, we found that even though MSP and
TGF-b are both capable of inducing EMT in MDCK cells, the complete epithelial-mesenchymal trans-differentiation
(ie, expressing specific mesenchymal cellular markers such as
a-smooth muscle actin) requires RON expression and
activation[69]. In MDCK cells that do not
express RON, neither TGF-b nor MSP alone is capable of inducing the expression of
a-smooth muscle actin. However, when RON is expressed,
TGF-b is able to induce a-smooth muscle actin
expression[69]. These results suggest that RON expression
is required for cell differentiation toward EMT with increased motile-invasive activities. As
both MSP and TGF-b are involved in regulating epithelial tumor motility, the signaling collaborations
between Smad 2 and RON might be essential in regulating invasive and metastatic potentials of certain epithelial cancers.
The signaling events of RON-mediated epithelial cell migration have been recently described using MSP-stimulated
human keratinocytes as a model[71]. In quiescent keratino-cytes, RON is physically associated with
a3b1 integrin, but free from a6b4 integrin that is associated with hemidesmo-some 1 and keratin filament leading to the formation of hemidesmosomes
(structures supporting cell adhesion). MSP stimulates the RON receptor resulting in the activation of
PI-3 kinase. The activated PI-3 kinase, through ATK kinase, phosphorylates both RON and
a6b4 integrin at specific 14-3-3 binding sites. Subsequently, a protein complex is formed between RON and
a6b4 integrin via 14-3-3 binding. This interaction prompts the
relocation of a6b4 integrin from its original place at hemidesmosomes to lamellipodia. During these events, hemidesmosomes
are gradually disassembled. The a3b1 integrin undergoes phosphorylation, is released from RON, and then moves to focal
contacts. Concomitant with these changes, keratinocytes started to spread and migrate on laminin-5 coated
membrane[71]. Thus, MSP induced epithelial cell migration is initiated through a mechanism in which RON forms a complex with
a6b4 integrin in a 14-3-3 dependent manner, which results in activation of
a3b1 integrin, disassembly of hemidesmosomes, and ultimately leads to cell spreading and migration.
Oncogenic signals Activated RON transduces a variety of signaling
pathways[10]. Currently, signaling proteins are
known to be activated by RON are
SOS[72], Grb2[72],
Ras[72], PI-3K[73,74], MAPK/Erk
1/2[61,63], JNK[49],
b-catenin[75], FAK[76],
integrins[77], Smad 2/3[69], and
NF-kB complex[78]. We have recently found that
b-arrestin-1, an adaptor protein for the seven transmembrane receptor family, is
also involved in RON-mediated signaling events (unpublished data). These proteins are
the effector molecules responsible for RON-mediated cell replication, transformation, migration, and matrix invasiveness.
Phosphorylation of tyrosine residues in the RON C-terminal tail results in the formation of a multifunctional docking
site[76,79]. The docking site, also known as the bidentate motif, is composed of a conserved sequence encompassing two
tyrosines
(Y1353VQL-XXX-Y1360MNL-)
[76,80]. Biochemical and biological studies have demonstrated that the docking site is
critical in recruiting intracellular components such as PI-3K, Grb2, and
others[79,80]. The substitution of
Y1353 and Y1360 with other amino acids results in the significant impairment of the docking site in interacting with signaling
proteins, which in turn leads to impaired cellular
functions[80]. Mutational analysis has indicated that this docking site is involved in RON-mediated
cell transformation. However, a recent study has shown that even though the docking site is required for the acquisition of
the full oncogenic phenotype, certain RON mutants, such as
RONM1254T, can exert cell transforming and metastatic activities
without the docking
site[80]. Consistent with these findings, a recent
in vitro study has shown that the bidentate motif in the C-terminal tail
inhibits RON kinase activities[81], suggesting that the C-terminal tail has a regulatory role that controls RON kinase catalytic
activities.
As described above, the oncogenic potentials of RON are determined by the catalytic efficiency of the kinase activity.
Currently, three mechanisms, overexpression, mutation, and truncation, are involved in the abnormal upregulation of the
RON kinase activity. The overexpression model is documented in mouse lung epithelial cells, in which the accumulation of
large amounts of wild-type RON results in constitutive activation of the kinase
activity[64]. The formation of tumors in RON
overexpressing lung epithelial cells, and not in control littermate
mice[64], indicates that increased RON kinase activity could
initiate unbalanced cell growth leading to tumor formation. The mutation model is observed in several experimentally created
RON mutants, in which highly conserved residues in the RON kinase domain, such as D1232V or M1254T, are
changed[61,63]. Substitution of these amino acid residues results in conformational changes in the kinase domain leading to a dramatic
increase in kinase activity. Thus, oncogenic activities are easily acquired by such manipulation. The truncation model is
observed in naturally occurring RON splicing variants such as
ROND160 and ROND155[65]. The deletion of the particular
extracellular regions encoded by exons 5, 6, and 11 results in increased kinase activity and tumorigenic activities. Detailed
analysis of amino acid sequences have shown that this deletion causes an unbalanced number of cysteine residues in the
extracellular domains of the RON variants resulting in the abnormal formation of intermolecular disulfide bonds. The
consequence of such abnormal bond formation is oligomerization of the altered receptor leading to increased kinase activities,
which are responsible for tumor formation in
vivo.
Potential target for therapeutic intervention
Pathogenic activities of RON in tumor progression provide the basis for targeting RON for therapeutic intervention. In
colon cancer cells, silencing the RON gene expression by siRNA techniques significantly affects cancer cell prolifera-tion,
soft agar growth, cellular motility, and increases apoptotic
death[60]. Moreover, blocking RON expression
greatly reduces Sw620 cell-mediated tumor growth
in vivo[60]. These results clearly show that RON is critical for maintaining tumorigenic
phenotypes. Thus, targeting RON expression should have a therapeutic potential to reverse malignant activities of colon
cancers in vivo.
Various strategies have been developed to block RON expression and its activation. Experimentally, inhibition of
MSP-induced activation by molecules that compete for MSP binding to RON is one approach. The soluble sema domain in the
RON b chain extracellular sequences has been shown to inhibit MSP-induced RON activation and associated cancer cell
proliferation[82]. The sema domain in the RON receptor is considered to be the MSP binding region. Another example is to use
siRNA-mediated gene silencing to inhibit RON expression and its signaling
events[60]. As described above, silencing RON
gene expression significantly inhibits tumor formation and growth by colon cancer Sw620 cells in a nude mouse model.
Therefore, RON-specific siRNA could have the potential to be delivered for therapeutic purposes. The third approach is to
use a dominant negative agent to inactivate RON or its oncogenic variant. We have used
ROND170 as a tool to block RON activation in cell models (unpublished
data). ROND170 is a splicing variant defective in the kinase
domain[52]. Preliminary studies indicate that this variant, when expressed in colon cancer cells, forms a heterodimeric complex
with wtRON and oncogenic ROND160 leading to diminished receptor phosphorylation and signaling transduction
(unpublished data). Thus, forced ROND170 expression as a gene therapy tool could have significance in reversing RON-mediated cancer-malignant
phenotypes.
Realistic approaches with the most clinical usefulness include monoclonal antibodies (mAbs) and small molecule inhibitors.
The development of a RON specific mAb is a very attractive idea. We have recently produced a panel of RON mAbs that
specifically target the RON extracellular domain. Obtained results from
in vitro studies have demonstrated that RON mAbs
have the potential to regulate oncogenic activities mediated by RON or its variants (unpublished data). These studies pave
the way for the development of RON mAb-based cancer therapy in the future.
Similar to other RTK such as EGFR, the RON tyrosine kinase is a candidate for small molecule inhibitors. Currently, small
molecules that specifically inhibit RON kinase activities have not been reported. Because of structural similarities between
MET and RON, selective small molecule inhibitors that target the kinase domain of both MET and RON have been
obtained[83]. A recently described PHA665752 seems to meet this criterion. PHA665752 was originally
discovered as a c-MET inhibitor with relatively improved
potency and selectivity (cellular Met kinase:
IC50, 0.042
µmol/L). It specifically blocks MET phosphorylation and associated tumor growth in mice in a dose-dependent
manner[83]. Studies have also confirmed that PHA665752 targets RON kinase activities with a relative specificity (cellular RON kinase:
IC50, 0.9 µmol/L)[83]. Thus, it is possible that RON-specific inhibitors could be identified through molecular designing.
Future direction
The progress in the last decade has dramatically increased our knowledge about the roles of RON in physiology and
pathogenesis. The discovery of aberrant expression and activation in primary cancer samples indicates that RON is involved
in the oncogenesis of epithelial tumors in
vivo. Moreover, abnormal RON activation is critical in regulating malignant
phenotypes of tumors. Thus, altered RON expression acts as a regulated invasiveness-promoting switch for the malignancy
of certain epithelial cancers. From this point of view, it is important to determine the pathogenic roles of RON and its variants
in the development of cancers such as colon and breast cancers. Furthermore, defining the relationships between the altered
RON expression, including the variant forms of RON, and the observed colon cancer phenotypes is also worth pursuing. In
this sense, mAb and small molecule inhibitor-based strategies to inactivate RON or its variants should provide important
information about the pathological role of RON in epithelial cancers. Considering these facts, altered RON expression could
be used as a cellular marker for early diagnosis and a pharmaceutical target for treatment of certain malignancies. Thus,
understanding the roles of RON in tumorigenesis in lung or colon cancers offers an opportunity to uncover the molecular
mechanisms underlying epithelial cancer pathogenesis. It should also hold potential for developing novel approaches to
control oncogenesis of certain epithelial tumors
in vivo.
Acknowledgements
The authors thank the colleagues in TTUHSC for their support and encouragement. We also thank Ms C SPIDEL for
editing the manuscript.
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