Tyrosine Kinase Ligand-Receptor Pair Prediction by Using Support Vector Machine
Masayuki YarimizuWei CaoYusuke KomiyamaKokoro UekiShugo NakamuraKazuya SumikoshiTohru TeradaKentaro Shimizu
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Abstract:
Receptor tyrosine kinases are essential proteins involved in cellular differentiation and proliferation in vivo and are heavily involved in allergic diseases, diabetes, and onset/proliferation of cancerous cells. Identifying the interacting partner of this protein, a growth factor ligand, will provide a deeper understanding of cellular proliferation/differentiation and other cell processes. In this study, we developed a method for predicting tyrosine kinase ligand-receptor pairs from their amino acid sequences. We collected tyrosine kinase ligand-receptor pairs from the Database of Interacting Proteins (DIP) and UniProtKB, filtered them by removing sequence redundancy, and used them as a dataset for machine learning and assessment of predictive performance. Our prediction method is based on support vector machines (SVMs), and we evaluated several input features suitable for tyrosine kinase for machine learning and compared and analyzed the results. Using sequence pattern information and domain information extracted from sequences as input features, we obtained 0.996 of the area under the receiver operating characteristic curve. This accuracy is higher than that obtained from general protein-protein interaction pair predictions.Keywords:
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Introduction: Tropomyosin-related kinase receptor C (TrkC) is a neurotrophin receptor that belongs to the tyrosine kinase receptor family. This family primarily consists of proto-oncogenes, and TrkC has been involved in oncogenic translocations. However, its expression in tumors is often associated with good prognosis, suggesting it actually acts as a tumor suppressor. TrkC has recently been demonstrated to be a dependence receptor, which regulates neuronal survival. Dependence receptors share the ability to trigger apoptosis in the absence of their ligand, a feature that has been suggested to confer a tumor suppressor function to these receptors. A selective advantage for a tumor cell to survive in an environment with limited ligand availability would hence be either to lose the expression of the dependence receptor, or to gain expression of its ligand.Areas covered: The role of neurotrophin-3 (NT-3) and its dependence receptor TrkC in neuroblastoma, and its suitability as a therapeutic target.Expert opinion: Autocrine production of NT-3 represents a selective advantage for tumor growth and dissemination, in a large fraction of aggressive neuroblastoma. Disruption of the NT-3 autocrine loop in malignant neuroblasts, triggers neuroblastoma cell death, and inhibits neuroblastoma metastasis in animal models. Thus, a novel way of targeting the tyrosine kinase receptor, is via the reactivation of its intrinsic ability to trigger cell death.
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Substitution of phenylalanine for tyrosine-809 in the human colony-stimulating factor 1 receptor (CSF-1R) inhibited its ability to transduce ligand-dependent mitogenic signals in mouse NIH 3T3 cells. When combined with an "activating" mutation at codon 301 that induces constitutive CSF-1R tyrosine kinase activity, the codon 809 mutation suppressed ligand-independent cell transformation. Comparative mapping of tryptic phosphopeptides from mutant and wild-type CSF-1R indicated that tyrosine-809 is a site of ligand-dependent receptor phosphorylation in vivo. The mutant receptor was active as a tyrosine kinase in vitro and in vivo, underwent CSF-1-dependent association with a phosphatidylinositol 3-kinase, and induced expression of the protooncogenes c-fos and junB, underscoring its ability to trigger some of the known cellular responses to CSF-1. The mutant receptor is likely to be impaired in its ability to interact with critical cellular effectors whose activity is required for mitogenesis.
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Human melanocytes respond to several growth factors whose receptors have tyrosine kinase activity. Abnormalities in the expression of tyrosine kinase receptors may play an important role in the initiation and progression of melanoma. We therefore determined the steady-state mRNA expression of five tyrosine kinase receptors, epidermal growth factor receptor (EGF-R), c-met, nerve growth factor receptor (NGF-R), colony-stimulating factor receptor (CSF-R) and c-kit, in eleven human melanoma cell lines with different metastatic potentials in nude mice. All cell lines except for one nonmetastatic line established from a primary melanoma lost expression of c-kit. Expression of the other four tyrosine kinase receptors varied among the lines. The expression level of individual tyrosine kinase receptor did not correlate with the metastatic potential of the cells. These results suggest that metastatic human melanoma cell lines are heterogeneous for expression of tyrosine kinase receptors, with each cell type manifesting a distinct repertoire of receptor tyrosine kinases. The different profile of tyrosine kinase activities in different metastatic melanomas complicates its use for prognosis.
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