Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase

Oncogenic activation of the met (hepatocyte growth factor/scatter factor) receptor tyrosine kinase involves a genomic rearrangement that generates a hybrid protein containing tpr-encoded sequences at its amino terminus fused directly to the met-encoded receptor kinase domain. Deletion of Tpr sequences abolishes the transforming ability of this protein, implicating this region in oncogenic activation. We demonstrate, by site-directed mutagenesis and coimmunoprecipitation experiments, that a leucine zipper motif within Tpr mediates dimerization of the tpr-met product and is essential for the transforming activity of the met oncogene. By analogy with ligand-stimulated activation of receptor tyrosine kinases, we propose that constitutive dimerization mediated by a leucine zipper motif within Tpr is responsible for oncogenic activation of the Met kinase. The possibility that this mechanism of activation represents a paradigm for a class of receptor tyrosine kinase oncogenes activated by DNA rearrangement is discussed.

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axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase.

Molecular and Cellular Biology ◽

10.1128/mcb.11.10.5016 ◽

1991 ◽

Vol 11 (10) ◽

pp. 5016-5031 ◽

Cited By ~ 467

Author(s):

J P O'Bryan ◽

R A Frye ◽

P C Cogswell ◽

A Neubauer ◽

B Kitch ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Kinase Domain ◽

Amino Acid Sequences ◽

Myelogenous Leukemia ◽

Fibronectin Type Iii ◽

Baculovirus System ◽

Nih 3T3 ◽

Transforming Gene

Using a sensitive transfection-tumorigenicity assay, we have isolated a novel transforming gene from the DNA of two patients with chronic myelogenous leukemia. Sequence analysis indicates that the product of this gene, axl, is a receptor tyrosine kinase. Overexpression of axl cDNA in NIH 3T3 cells induces neoplastic transformation with the concomitant appearance of a 140-kDa axl tyrosine-phosphorylated protein. Expression of axl cDNA in the baculovirus system results in the expression of the appropriate recombinant protein that is recognized by antiphosphotyrosine antibodies, confirming that the axl protein is a tyrosine kinase. The juxtaposition of fibronectin type III and immunoglobulinlike repeats in the extracellular domain, as well as distinct amino acid sequences in the kinase domain, indicate that the axl protein represents a novel subclass of receptor tyrosine kinases.

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axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase

Molecular and Cellular Biology ◽

10.1128/mcb.11.10.5016-5031.1991 ◽

1991 ◽

Vol 11 (10) ◽

pp. 5016-5031

Author(s):

J P O'Bryan ◽

R A Frye ◽

P C Cogswell ◽

A Neubauer ◽

B Kitch ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Kinase Domain ◽

Amino Acid Sequences ◽

Myelogenous Leukemia ◽

Fibronectin Type Iii ◽

Baculovirus System ◽

Nih 3T3 ◽

Transforming Gene

Using a sensitive transfection-tumorigenicity assay, we have isolated a novel transforming gene from the DNA of two patients with chronic myelogenous leukemia. Sequence analysis indicates that the product of this gene, axl, is a receptor tyrosine kinase. Overexpression of axl cDNA in NIH 3T3 cells induces neoplastic transformation with the concomitant appearance of a 140-kDa axl tyrosine-phosphorylated protein. Expression of axl cDNA in the baculovirus system results in the expression of the appropriate recombinant protein that is recognized by antiphosphotyrosine antibodies, confirming that the axl protein is a tyrosine kinase. The juxtaposition of fibronectin type III and immunoglobulinlike repeats in the extracellular domain, as well as distinct amino acid sequences in the kinase domain, indicate that the axl protein represents a novel subclass of receptor tyrosine kinases.

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Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

Pharmaceuticals ◽

10.3390/ph14070626 ◽

2021 ◽

Vol 14 (7) ◽

pp. 626

Author(s):

Julie Bolcaen ◽

Shankari Nair ◽

Cathryn H. S. Driver ◽

Tebatso M. G. Boshomane ◽

Thomas Ebenhan ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Radionuclide Therapy ◽

Kinase Inhibitors ◽

Nuclear Imaging ◽

Therapy Resistance ◽

Targeted Radionuclide Therapy ◽

Therapy Strategy ◽

Dismal Prognosis

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

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Signaling in new directions

Biochemistry and Cell Biology ◽

10.1139/o95-016 ◽

1995 ◽

Vol 73 (3-4) ◽

pp. 133-136 ◽

Cited By ~ 2

Author(s):

Haleh Vahidi Samiei

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Tyrosine Kinase ◽

Map Kinase ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Molecular Level ◽

Clear Cut ◽

New Directions

Many laboratories, using a variety of organisms, have contributed to deciphering the identity and the order of the components leading from ligand-bound receptor tyrosine kinases to various intracellular events, including changes in gene expression. The gaps have only been filled recently. This minireview summarizes the findings and points out the degree of conservation of the same pathway in distant organisms, both at the molecular level and in terms of the consecutive steps. The review also looks at points at which this pathway might be diverging and points onto which other pathways might be converging. These interactions are not always clear cut, and understanding them will be the challenge for the future.Key words: signal transduction, receptor tyrosine kinase, RAS, RAF, MAP kinase.

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Functional dissection of p56lck, a protein tyrosine kinase which mediates interleukin-2-induced activation of the c-fos gene

Molecular and Cellular Biology ◽

10.1128/mcb.14.9.5812-5819.1994 ◽

1994 ◽

Vol 14 (9) ◽

pp. 5812-5819

Author(s):

H Shibuya ◽

K Kohu ◽

K Yamada ◽

E L Barsoumian ◽

R M Perlmutter ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinases ◽

Protein Tyrosine Kinase ◽

Gene Activation ◽

Interleukin 2 ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Amino Acid Residues ◽

Protein Tyrosine ◽

Responsive Element

Members of the newly identified receptor family for cytokines characteristically lack the intrinsic protein tyrosine kinase domain that is a hallmark of other growth factor receptors. Instead, accumulating evidence suggests that these receptors utilize nonreceptor-type protein tyrosine kinases for downstream signal transduction by cytokines. We have shown previously that the interleukin-2 receptor beta-chain interacts both physically and functionally with a Src family member, p56lck, and that p56lck activation leads to induction of the c-fos gene. However, the mechanism linking p56lck activation with c-fos induction remains unelucidated. In the present study, we systematically examined the extent of c-fos promoter activation by expression of a series of p56lck mutants, using a transient cotransfection assay. The results define a set of the essential amino acid residues that regulate p56lck induction of the c-fos promoter. We also provide evidence that the serum-responsive element and sis-inducible element are both targets through which p56lck controls c-fos gene activation.

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Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions

Cells ◽

10.3390/cells9020513 ◽

2020 ◽

Vol 9 (2) ◽

pp. 513 ◽

Cited By ~ 1

Author(s):

Marina Leite ◽

Miguel S. Marques ◽

Joana Melo ◽

Marta T. Pinto ◽

Bruno Cavadas ◽

...

Keyword(s):

Helicobacter Pylori ◽

Tyrosine Kinase ◽

Signaling Pathways ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Receptor Activation ◽

Degradation Pathway ◽

Mrna Levels ◽

H Pylori

Helicobacter pylori, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, H. pylori continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using two different gastric epithelial cell lines, we show that H. pylori targets the receptor tyrosine kinase EPHA2. For long periods of time post-infection, H. pylori induces EPHA2 protein downregulation without affecting its mRNA levels, an effect preceded by receptor activation via phosphorylation. EPHA2 receptor downregulation occurs via the lysosomal degradation pathway and is independent of the H. pylori virulence factors CagA, VacA, and T4SS. Using small interfering RNA, we show that EPHA2 knockdown affects cell–cell and cell–matrix adhesion, invasion, and angiogenesis, which are critical cellular processes in early gastric lesions and carcinogenesis mediated by the bacteria. This work contributes to the unraveling of the underlying mechanisms of H. pylori–host interactions and associated diseases. Additionally, it raises awareness for potential interference between H. pylori infection and the efficacy of gastric cancer therapies targeting receptors tyrosine kinases, given that infection affects the steady-state levels and dynamics of some receptor tyrosine kinases (RTKs) and their signaling pathways.

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Only the Substitution of Methionine 918 with a Threonine and Not with Other Residues Activates RET Transforming Potential*

Endocrinology ◽

10.1210/endo.138.4.5073 ◽

1997 ◽

Vol 138 (4) ◽

pp. 1450-1455 ◽

Cited By ~ 2

Author(s):

Anna Maria Cirafici ◽

Giuliana Salvatore ◽

Gabriella De Vita ◽

Francesca Carlomagno ◽

Nina A. Dathan ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Point Mutations ◽

Early Response ◽

Specific Point ◽

Medullary Thyroid ◽

Transforming Activity ◽

Early Response Genes

Abstract Specific point-mutations of the RET receptor tyrosine kinase protooncogene are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). MEN2B is caused by the substitution of methionine 918 by a threonine in the tyrosine kinase (TK) domain of RET. This mutation converts RET into a dominant transforming oncogene. We have substituted Met918 with four different residues and found that RET acquired transforming activity only when Met918 was substituted with a threonine. However, also when serine and valine, but not leucine or phenylalanine, were inserted in position 918, the RET TK function was activated and induced, especially in the case of the RET(918Ser), immmediate-early response genes. We conclude that the preservation of Met918 is critical for the control of RET kinase. However, only when a threonine residue is present in position 918, does RET efficiently couple with a transforming pathway.

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Characterization of elk, a brain-specific receptor tyrosine kinase

Molecular and Cellular Biology ◽

10.1128/mcb.11.5.2496-2502.1991 ◽

1991 ◽

Vol 11 (5) ◽

pp. 2496-2502

Author(s):

V Lhoták ◽

P Greer ◽

K Letwin ◽

T Pawson

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Protein Tyrosine Kinase ◽

Catalytic Domain ◽

Signal Sequence ◽

Tyrosine Kinase Domain ◽

Rat Tissues ◽

Protein Tyrosine

The elk gene encodes a novel receptorlike protein-tyrosine kinase, which belongs to the eph subfamily. We have previously identified a partial cDNA encompassing the elk catalytic domain (K. Letwin, S.-P. Yee, and T. Pawson, Oncogene 3:621-678, 1988). Using this cDNA as a probe, we have isolated cDNAs spanning the entire rat elk coding sequence. The predicted Elk protein contains all the hallmarks of a receptor tyrosine kinase, including an N-terminal signal sequence, a cysteine-rich extracellular domain, a membrane-spanning segment, a cytoplasmic tyrosine kinase domain, and a C-terminal tail. In both amino acid sequence and overall structure, Elk is most similar to the Eph and Eck protein-tyrosine kinases, suggesting that the eph, elk, and eck genes encode members of a new subfamily of receptorlike tyrosine kinases. Among rat tissues, elk expression appears restricted to brain and testes, with the brain having higher levels of both elk RNA and protein. Elk protein immunoprecipitated from a rat brain lysate becomes phosphorylated on tyrosine in an in vitro kinase reaction, consistent with the prediction that the mammalian elk gene encodes a tyrosine kinase capable of autophosphorylation. The characteristics of the Elk tyrosine kinase suggest that it may be involved in cell-cell interactions in the nervous system.

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TYRO3: A potential therapeutic target in cancer

Experimental Biology and Medicine ◽

10.1177/1535370219828195 ◽

2019 ◽

Vol 244 (2) ◽

pp. 83-99 ◽

Cited By ~ 3

Author(s):

Pei-Ling Hsu ◽

Jonathan Jou ◽

Shaw-Jenq Tsai

Keyword(s):

Molecular Biology ◽

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Epithelial Mesenchymal Transition ◽

Protein S ◽

Targeted Treatment ◽

Novel Therapy ◽

Mesenchymal Transition ◽

Promote Cell Proliferation

TYRO3 belongs to the TAM (TYRO3, AXL, and MER) receptor family, a unique subfamily of the receptor tyrosine kinases. Members of TAM family share the same ligand, growth arrest-specific 6, and protein S. Although the signal transduction pathways of TYRO3 have not been evaluated in detail, overexpression and activation of TYRO3 receptor tyrosine kinase have been reported to promote cell proliferation, survival, tumorigenesis, migration, invasion, epithelial-mesenchymal transition, or chemoresistance in several human cancers. Targeting TYRO3 could break the kinase signaling, stimulate antitumor immunity, reduce tumor cell survival, and regain drug sensitivity. To date, there is no specific TYRO3-targeted drug, the effectiveness of targeting TYRO3 in cancer is worthy of further investigations. In this review, we present an update on molecular biology of TYRO3, summarize the development of potential inhibitors of TAM family members, and provide new insights in TYRO3-targeted treatment. Impact statement Cancer is among the leading causes of death worldwide. In 2016, 8.9 million people are estimated to have died from various forms of cancer. The current treatments, including surgery with chemotherapy and/or radiation therapy, are not effective enough to provide full protection from cancer, which highlights the need for developing novel therapy strategies. In this review, we summarize the molecular biology of a unique member of a subfamily of receptor tyrosine kinase, TYRO3 and discuss the new insights in TYRO3-targeted treatment for cancer therapy.

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