scholarly journals Survival of the weakest: signaling aided by endosomes

2008 ◽  
Vol 182 (5) ◽  
pp. 823-825 ◽  
Author(s):  
Marisa P. McShane ◽  
Marino Zerial
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Cell Biology ◽  
Tyrosine Kinase Receptor ◽  
Endosomal Trafficking ◽  
Spatiotemporal Regulation ◽  
Molecular Machinery ◽  
Factor C ◽  
Hepatocyte Growth ◽  
Major Target

The tyrosine kinase receptor c-Met plays a key role in cell proliferation, morphogenesis, and motility in response to hepatocyte growth factor. C-Met is often altered in cancer and is a major target for therapeutic intervention. Despite knowing a great deal of the molecular machinery downstream of this receptor tyrosine kinase, the spatiotemporal regulation of c-Met signaling still remains elusive. In this issue of the Journal of Cell Biology, Kermorgant and Parker (Kermorgant, S. and P.J. Parker. 2008. J. Cell Biol. 182:855–863) provide evidence for a model in which the c-Met–activated STAT3 signal is mediated by endosomal trafficking. This study elegantly highlights how weak signals can be effectively transmitted to the nucleus by exploiting endosomal compartments, raising important mechanistic implications for the signaling research community.

scholarly journals Cardiovascular Effects in Rats following Exposure to a Receptor Tyrosine Kinase Inhibitor

2010 ◽  
Vol 38 (3) ◽  
pp. 416-428 ◽  
Author(s):  
Shirley A. Aguirre ◽  
Jonathan R. Heyen ◽  
Walter Collette ◽  
Walter Bobrowski ◽  
Eileen R. Blasi
Keyword(s):  
Cardiac Function ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Cardiovascular Effects ◽  
Tyrosine Kinase Receptor ◽  
Sprague Dawley ◽  
Treatment Data ◽  
Factor C

The receptor tyrosine kinase receptor (RTK) signaling pathway, mesenchymal-epithelial transition factor (c-Met)/hepatocyte growth factor receptor (HGFR), has been implicated in oncogenesis and is a target of interest in cancer therapy. PF-04254644 is a potent and selective inhibitor of c-Met/HGFR. Wide ligand binding profiling of PF-04254644 revealed a potentially significant interaction with phosphodiesterase (PDE) 3, and follow-up PDE enzyme activity assays confirmed PF-04254644 as a potent inhibitor of PDE3 as well as other PDEs (1, 2, 5, 10, and 11). Clinical observations, laboratory, and echocardiography parameters were recorded in Sprague-Dawley (SD) rats that received PF-04254644 oral dosing for up to seven consecutive days. Toxicological evaluations revealed myocardial degeneration as an adverse event at all tested doses. Echocardiographic evaluations revealed an increase in heart rate (HR) and contractility after the first dose with PF-04254644 and myocardial fibrosis correlated with decreased cardiac function after repeat dosing. A study in telemetry-instrumented rats substantiated that PF-04254644 induced a sustained increased HR and decreased contractility after six days of treatment. Data suggest that the decreased cardiac function and cardiotoxicity are likely due to inhibition of multiple PDEs by PF-04254644.

scholarly journals Steel factor and c-kit regulate cell-matrix adhesion

Blood ◽  
1994 ◽  
Vol 83 (4) ◽  
pp. 1033-1038 ◽  
Author(s):  
T Kinashi ◽  
TA Springer
Keyword(s):  
Mast Cells ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Primordial Germ Cells ◽  
Growth Stimulation ◽  
Interleukin 4 ◽  
Tyrosine Kinase Receptor ◽  
Steel Factor ◽  
Matrix Adhesion ◽  
Factor C

Abstract Steel (SI) and white spotting (W) loci encode steel factor (c-kit ligand) and the c-kit tyrosine kinase receptor, respectively. Mutations at these loci affect migration and differentiation of primordial germ cells, neural crest-derived melanoblasts, and hematopoietic cells. In these processes, cell adhesion molecules are hypothesized to be crucial. We have examined the role of steel factor and c-kit in cell- extracellular matrix adhesion using bone marrow-derived mast cells as a model system. Steel factor stimulates mast cells to bind to fibronectin and, to a lesser extent, to vitronectin, whereas interleukin-3 and interleukin-4, which are also mast cell growth factors, do not. Activation of adhesiveness is transient, occurs at concentrations of steel factor 100-fold lower than required for growth stimulation, and requires the integrin VLA-5. Mast cells from c-kit mutant mice adhere to fibronectin on stimulation with phorbol 12-myristate 13-acetate (PMA), but not on stimulation with steel factor, indicating that stimulation of integrin adhesiveness requires activation of the c-kit protein tyrosine kinase. By contrast, c-kit mutant and wild-type mast cells adhere equally well to COS cells expressing membrane-anchored steel factor, showing that the kinase activity of c-kit is not required for adhesion directly mediated by c-kit. Our findings suggest that regulation of adhesion is an important biologic function of steel factor.

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

1993 ◽  
Vol 13 (11) ◽  
pp. 6711-6722 ◽  
Author(s):  
G A Rodrigues ◽  
M Park
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Leucine Zipper ◽  
Kinase Domain ◽  
Site Directed Mutagenesis ◽  
Leucine Zipper Motif ◽  
Transforming Activity ◽  
Met Oncogene ◽  
Hepatocyte Growth

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.

scholarly journals Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications

2020 ◽  
Vol 295 (18) ◽  
pp. 5995-6006 ◽  
Author(s):  
Rebecca S. Goydel ◽  
Justus Weber ◽  
Haiyong Peng ◽  
Junpeng Qi ◽  
Jo Soden ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Cancer Therapeutics ◽  
Affinity Maturation ◽  
Fine Tuning ◽  
Orphan Receptor ◽  
Tyrosine Kinase Receptor ◽  
Cell Surface Antigens ◽  
Complementarity Determining Region

Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.

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