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Query: UNIPROT:P06889 (Mol)
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Receptor tyrosine kinases (RTK) with five, three, or seven immunoglobulinlike domains in their extracellular regions are classified as subclasses III, IV, and V, respectively. Conservation of the exon/intron structure of the downstream part of the human KIT, FMS, and FLT3 genes that encode RTK of subclass III together with the particular chromosomal localization of these genes suggests that RTKIII genes have evolved from a common ancestor by cis and trans duplications. To strengthen this model of evolution and to determine if it can be extended to RTKIV and V genes, we constructed a phylogenetic tree of RTKIII, IV, and V on the basis of a multiple alignment of their catalytic tyrosine kinase domain sequences and determined the exon/intron structure of PDGFRA (subclass III), FGFR4 (subclass IV), and FLT4 (subclass V) genes in their downstream part. Phylogenetic analyses with amino acid or nucleotide sequences both resulted in one most parsimonious tree. The phylogenetic trees obtained indicate that all three subclasses are well individuated and that RTKIII and RTKV are closer to each other than RTKIV. Furthermore, RTKIII and FLT4 (subclass V) genes possess the same exon/intron structure in their downstream part while the structure of the RTKIV genes is very similar to that of RTKIII and FLT4. Both approaches are in complete agreement and indicate that RTKIII, IV, and V genes most probably evolved from a common ancestor already "in pieces" by successive duplications involving entire genes.
J Mol Evol 1995 Oct
PMID:Molecular evolution of the genes encoding receptor tyrosine kinase with immunoglobulinlike domains. 756 29

Receptor tyrosine kinases with five, seven, and three Ig-like domains in their extracellular region are grouped in subclasses IIIa, IIIb, and IIIc, respectively. Here, we describe the genomic organization of the extracellular coding region of the human FGFR4 (IIIc) and FLT4 (IIIb) genes and compare it to that of the human FGFR1(IIIc), KIT, and FMS (IIIa). The results show that while genes belonging to the same subclass have an identical exon/intron structure in their extracellular coding region-as they do in their intracellular coding region-genes of related subclasses only have a similar exon/intron structure. These results strongly support the hypothesis that the genes of the three subclasses evolved from a common ancestor by duplications involving entire genes, already in pieces. Hypotheses on the origin of introns and on the difference in the number of extracellular Ig-like domains in the three gene subclasses are discussed.
J Mol Evol 1997 Jul
PMID:Genomic organization of the extracellular coding region of the human FGFR4 and FLT4 genes: evolution of the genes encoding receptor tyrosine kinases with immunoglobulin-like domains. 921 33

Chronic myeloid leukaemia (CML) is characterized by the presence of the BCR-ABL fusion gene, usually in association with the t(9;22)(q34;q11) translocation. We report here the identification and cloning of a rare variant translocation, t(4;22)(q12;q11), in two patients with a CML-like myeloproliferative disease (MPD). RT-PCR indicated that both patients were negative for BCR-ABL, but FISH analysis suggested that the BCR gene was rearranged. Since other translocations in MPDs frequently involve tyrosine kinases, we designed a multiplex PCR to search for mRNA fusions between BCR and three potential partner genes at 4q12: KIT, KDR and PDGFRA. An unusual inframe BCR-PDGFRA fusion mRNA was identified in both patients, with either BCR exon 7 or exon 12 fused to short BCR intron-derived sequences, which were in turn fused to part of PDGFRA exon 12. Sequencing of the genomic breakpoint junctions showed that the chromosome 22 breakpoints fell in BCR introns whereas the chromosome 4 breakpoints were within PDGFRA exon 12. This is the first report of a fusion gene that involves PDGFRA. Our findings indicate that apparently simple cytogenetic variants of t(9;22) do not always mask a cryptic BCR-ABL fusion, even when found in association with clinical and haematological indications of CML.
Hum Mol Genet 2002 Jun 01
PMID:The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. 1202 81

Gastrointestinal stromal tumors are the most common mesenchymal neoplasms of the digestive tract. These tumors express the c-kit receptor tyrosine kinase, and many have activating mutations in the juxtamembrane region coded by the exon 11 of KIT. Detection of these mutations has prognostic and therapeutic impact. The aim of the study was to compare a new detection method by length analysis of polymerase chain reaction products (LAPP) to direct sequencing. The detection of either deletion or insertion mutations within the exon 11 of KIT was performed on genomic DNA extracted from 40 paraffin-embedded samples from 38 patients. Double-strand direct sequencing revealed a mutation in 25 of 40 samples. In two additional samples, a mutation was suspected but could not be determined by sequencing. LAPP revealed a mutation in 27 samples, corresponding to the 25 determined and 2 suspected samples. One of these latter samples contained three different alleles. Mutations corresponded to either deletions (n = 24) or insertion (n = 1) and had the same size with sequencing and LAPP. Our results show that LAPP is as accurate and more sensitive than direct sequencing for the detection of deletion or insertion mutations of exon 11 of KIT in gastrointestinal stromal tumors.
Diagn Mol Pathol 2002 Jun
PMID:Length analysis of polymerase chain reaction products: a sensitive and reliable technique for the detection of mutations in KIT exon 11 in gastrointestinal stromal tumors. 1204 14

Immunohistochemical staining for KIT (CD117) was performed on 144 cases of soft tissue sarcoma and 11 cases of gastrointestinal stromal tumor (GIST). Diffuse global staining in almost all neoplastic cells was a consistent feature of GIST but was also seen in some types of soft tissue sarcoma that resemble GISTs morphologically, such as synovial sarcoma and leiomyosarcoma. This finding is of diagnostic importance because some of these sarcoma types may involve the intestinal wall and simulate primary GIST. Most other positive cases showed focal staining. Although focal positivity may not be a problem in resected specimens, it has the potential to be misleading in biopsy material. Our results are concordant with some reports of CD117 expression in soft tissue tumors, but they differ from those reported by other laboratories. This discrepancy in the literature may be the result of variation in antibodies used or variation in immunohistochemical staining protocol. Regardless of the technical or scientific explanation, an understanding of the difficulties with KIT immunostaining is critical. Not only is KIT positivity used as a prerequisite for the diagnosis of GISTs, but treatment eligibility for STI571 in patients with GIST, and increasingly with other tumors, relies on positive KIT immunostaining.
Appl Immunohistochem Mol Morphol 2003 Mar
PMID:The problem with KIT: clinical implications and practical difficulties with CD117 immunostaining. 1261 Mar 58

The purpose of this study was to evaluate the activity of the indolinone kinase inhibitor SU11248 against the receptor tyrosine kinase KIT in vitro and in vivo, examine the role of KIT in small cell lung cancer (SCLC), and anticipate clinical utility of SU11248 in SCLC. SU11248 is an oral, multitargeted tyrosine kinase inhibitor with direct antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, KIT, and FLT3 receptors. Treatment of the KIT-expressing SCLC-derived NCI-H526 cell line in vitro with SU11248 resulted in dose-dependent inhibition of stem cell factor-stimulated KIT phosphotyrosine levels and proliferation. The biological significance of KIT inhibition was evaluated in vivo by treating mice bearing s.c. NCI-H526 tumors with SU11248 or another structurally unrelated KIT inhibitor, STI571 (Gleevec), which is also known to inhibit Bcr-Abl and PDGFRbeta. SU11248 treatment resulted in significant tumor growth inhibition, whereas inhibition from STI571 treatment was less dramatic. Both compounds reduced phospho-KIT levels in NCI-H526 tumors, with a greater reduction by SU11248, correlating with efficacy. Likewise, phospho-PDGFRbeta levels contributed by tumor stroma and with known involvement in angiogenesis were strongly inhibited by SU11248 and less so by STI571. Because platinum-based chemotherapy is part of the standard of care for SCLC, SU11248 was combined with cisplatin, and significant tumor growth delay was measured compared with either agent alone. These results expand the profile of SU11248 as a KIT signaling inhibitor and suggest that SU11248 may have clinical potential in the treatment of SCLC via direct antitumor activity mediated via KIT as well as tumor angiogenesis via vascular endothelial growth factor receptor FLK1/KDR and PDGFRbeta.
Mol Cancer Ther 2003 May
PMID:SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. 1274 9

The sensory receptors for hearing and balance are the hair cells of the cochlea and vestibular organs of the inner ear. Permanent hearing and balance deficits can be triggered by genetic susceptibilities or environmental factors such as infection. Unlike mammalian hair cells that have a limited capacity for regeneration, the vestibular organ of the avian ear is constantly undergoing hair cell regeneration, whereas the avian cochlea undergoes regeneration only when hair cells are damaged. In order to gain insights into the genetic programs that govern the regenerative capacity of hair cells, we interrogated custom human cDNA microarrays with sensory epithelial cell targets from avian inner ears. The arrays contained probes from conserved regions of approximately 400 genes expressed primarily in the inner ear and approximately 1500 transcription factors (TF). Highly significant differences were observed for 20 inner-ear genes and more than 80 TFs. Genes up-regulated in the cochlea included BMP4, GATA3, GSN, FOXF1 and PRDM7. Genes up-regulated in the utricle included SMAD2, KIT, beta-AMYLOID, LOC51637, HMG20B and CRIP2. Many of the highly significant changes were validated by Q-PCR and in situ methods. Some of the observed changes implicated a number of known biochemical pathways including the c-kit pathway previously observed in melanogenesis. Twenty differentially expressed TFs map to chromosomal regions harboring uncloned human deafness loci, and represent novel candidates for hearing loss. The approach described here also illustrates the power of utilizing conserved human cDNA probes for cross-species comparisons.
Hum Mol Genet 2003 Jun 01
PMID:Gene expression differences in quiescent versus regenerating hair cells of avian sensory epithelia: implications for human hearing and balance disorders. 1276 Oct 41

Gastrointestinal stromal tumors (GISTs), defined by the presence of constitutively activated KIT, are the most common gastrointestinal mesenchymal malignancies. This observation has been successfully exploited in clinical trials of Gleevec (also known as imatinib mesylate, STI-571) for patients with unresectable and/or metastatic GISTs. The biological mechanisms of Gleevec as well as its downstream molecular effects are generally unknown. We used a DNA microarray-based approach to identify gene expression patterns and signaling pathways that were altered in response to Gleevec in GIST cells. We identified a total of 148 genes or expressed sequence tags (of 10,367) that were differentially regulated; 7 known genes displayed a durable response after treatment. The significantly down-regulated genes were SPRY4A, FZD8, PDE2A, RTP801, FLJ20898, and ARHGEF2. The only up-regulated gene was MAFbx. On a functional level, we demonstrated that imatinib inhibited phosphorylation of KIT, AKT, and extracellular signal-regulated kinase 1/2 without affecting the total level of these proteins and that differential expression of these response genes involved activation of mitogen-activated protein kinase-dependent and -independent pathways. In an attempt to correlate these in vitro findings to clinical data, we examined GIST needle biopsy specimens taken from patients before and after Gleevec administration according to the CSTI571-B2222 Phase II trial and demonstrated that expression levels of the two gene transcripts evaluated correlated well with clinical response. This study emphasizes the potential value of an in vitro cell model to investigate GIST response to imatinib in vivo, for the purpose of identifying important genetic markers of clinical response, mechanisms of drug action, and possible therapeutic targets.
Mol Cancer Ther 2003 Aug
PMID:Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors. 2207 11

SU11248 is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities through targeting platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and FLT3, the first three of which are expressed in human breast cancer and/or its supporting tissues. The purpose of the present studies was to demonstrate the potent anticancer activity of SU11248 alone or in combination with conventional cytotoxic agents against several distinct preclinical models of breast cancer. SU11248 was administered as a monotherapy to (1) mouse mammary tumor virus-v-Ha-ras mice and 7,12-dimethylbenz(a)anthracene-treated rats bearing mammary tumors and (2) mice bearing human breast cancer xenografts of s.c. MX-1 tumors and osseous metastasis of a MDA-MB-435-derived cell line (435/HAL-Luc). SU11248 was also administered in combination with docetaxel both in xenograft models and in combination with 5-fluorouracil and doxorubicin in the MX-1 model. SU11248 treatment potently regressed growth of mammary cancers in mouse mammary tumor virus-v-Ha-ras transgenic mice (82% regression) and 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats (99% regression at the highest dose; P < 0.05 for both). This agent also inhibited MX-1 tumor growth by 52%, with markedly enhanced anticancer effects when administered in combination with docetaxel, 5-fluorouracil, or doxorubicin compared with either agent alone (P < 0.05). SU11248 treatment in combination with docetaxel effectively prolonged survival of mice, with 435/HAL-Luc cancer xenografts established in bone compared with either agent alone (P < 0.05). These results demonstrate that SU11248 is effective in preclinical breast cancer models and suggest that it may be useful in the treatment of breast cancer in the clinic.
Mol Cancer Ther 2003 Oct
PMID:Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. 1457 66

It is known that Notch activation promotes the self-renewal of hematopoietic cells. However, we have previously found that the growth of a myeloid leukemia cell line, OCI/AML-6, was suppressed by Notch activation induced by stimulation with a recombinant Notch ligand, Delta-1 protein. We recently found that the growth of another leukemia cell line, THP-1, was also suppressed by the ligands Delta-1 and Jagged-1. In this study, we tried to clarify the cellular and molecular mechanism of the growth suppression induced by Notch activation. Flow cytometric analysis showed that Delta-1 stimulation increased the expression of differentiation markers such as CD11b and CD13 while it decreased the expression of CD117 (c-KIT), a marker for primitive cells in THP-1 cells. In OCI/AML-6 cells, Delta-1 stimulation decreased the expression of CD11b and CD14 and increased CD34 expression. Namely, Delta-1 showed the opposite effects on the differentiation markers of each cell line. Delta-1 stimulation did not increase the binding of annexin V, a marker for apoptotic cells in either cell line. Since the growth of myeloid cells is regulated by MAP kinase and JAK/STAT pathways, we investigated the effects of the ligand stimulation on these pathways. Delta-1 stimulation did not induce the phosphorylation of ERK1/2 and STAT3 proteins in either cell line. Pre-exposure to Delta-1 did not affect the phosphorylation of ERK1/2 and STAT3 induced by G-CSF in OCI/AML-6 cells, either. Namely, it is thought that these pathways are not involved in the growth suppression caused by Notch ligands. Our study revealed several findings on Notch function. However, the precise mechanism remains to be elucidated.
Int J Mol Med 2004 Aug
PMID:Cellular analysis of growth suppression induced by the Notch ligands, Delta-1 and Jagged-1 in two myeloid leukemia cell lines. 1525 69


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