scholarly journals Genetic interactions between the Drosophila Abelson (Abl) tyrosine kinase and failed axon connections (fax), a novel protein in axon bundles.

Genetics ◽  
1995 ◽  
Vol 141 (2) ◽  
pp. 595-606 ◽  
Author(s):  
K K Hill ◽  
V Bedian ◽  
J L Juang ◽  
F M Hoffmann
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Essential Gene ◽  
Protein Product ◽  
Genetic Interactions ◽  
Loss Of Function ◽  
Wild Type ◽  
Abl Tyrosine Kinase ◽  
The Central Nervous System ◽  
Novel Protein

Abstract Mutations in the failed axon connections (fax) gene have been identified as dominant genetic enhancers of the Abl mutant phenotype. These mutations in fax all result in defective or absent protein product. In a genetic background with wild-type Abl function, the fax loss-of-function alleles are homozygous viable, demonstrating that fax is not an essential gene unless the animal is also mutant for Abl. The fax gene encodes a novel 47-kD protein expressed in a developmental pattern similar to that of Abl in the embryonic mesoderm and axons of the central nervous system. The conditional, extragenic noncomplementation between fax and another Abl modifier gene, disabled, reveal that the two proteins are likely to function together in a process downstream or parallel to the Abl protein tyrosine kinase.

Beaded of Goldschmidt, an Antimorphic Allele of Serrate, Encodes a Protein Lacking Transmembrane and Intracellular Domains

Genetics ◽  
1997 ◽  
Vol 145 (2) ◽  
pp. 359-374 ◽  
Author(s):  
Neil A Hukriede ◽  
Robert J Fleming
Keyword(s):  
Essential Gene ◽  
Protein Product ◽  
Homologous Region ◽  
Wing Margin ◽  
Loss Of Function ◽  
Wild Type ◽  
Rich Region ◽  
Coding Regions ◽  
Dna Lesion ◽  
Intracellular Domains

Serrate (Ser) is an essential gene in Drosophila melanogaster best known for the Ser dominant (SerD) allele and its effects on wing development. Animals heterozygous or homozygous for (SerD) are viable and exhibit loss of wing margin tissue and associated bristles and hairs. The Beaded of Goldschmidt (BdG) allele of Ser, when heterozygous to wild type, will also produce animals exhibiting loss of wing margin material. However, animals homozygous for BdG exhibit a larval lethal phenotype comparable to animals homozygous for loss-of-function Ser alleles. BdG is a partial duplication of the Ser locus with a single 5′ Ser-homologous region and two distinct 3′ regions. Meiotic recombination between BdG and a wild-type Ser chromosome demonstrated that only one DNA lesion, caused by the insertion of a transposable roo element into the coding regions of the Ser transcript, appears capable of generating BdG phenotypes. Due to the roo insertion, the protein product is predicted to be prematurely truncated and lack an extracellular cysteine-rich region along with the transmembrane and intracellular domains found within the normal SERRATE (SER) protein. The loss of these protein domains apparently contributes to the antimorphic nature of this mutation.

A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation

Blood ◽  
2006 ◽  
Vol 108 (5) ◽  
pp. 1716-1723 ◽  
Author(s):  
Lynn McCallum ◽  
Susan Price ◽  
Nathalie Planque ◽  
Bernard Perbal ◽  
Andrew Pierce ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Direct Consequence ◽  
Suppressor Gene ◽  
Hematopoietic Stem ◽  
Protein Levels ◽  
Abl Kinase ◽  
Abl Tyrosine Kinase ◽  
Ccn3 Expression

Chronic myeloid leukemia (CML) is characterized by the presence of the constitutively active BCR-ABL protein tyrosine kinase. Using a multipotent hemopoietic cell line, FDCP-Mix, expressing BCR-ABL tyrosine kinase, we investigated the initial effects of this kinase in primitive hematopoietic stem cells. We identified down-regulation of a novel gene, CCN3, as a direct consequence of BCR-ABL kinase activity. CCN3 has been reported to function as a tumor suppressor gene in solid tumors. Northern and Western blotting plus immunocytochemical analysis confirmed CCN3 expression is decreased and is tyrosine-phosphorylated in BCR-ABL kinase active FDCP-Mix cells. Decreased cellular CCN3 correlated with increased CCN3 secretion in BCR-ABL kinase active cells. In vitro treatment of human CML cell lines with imatinib or siRNA directed against BCR-ABL significantly reduced BCR-ABL while increasing CCN3 expression. Cells from patients responding to imatinib showed a similar decrease in BCR-ABL and increase in CCN3. CML CD34+ cells treated with imatinib in vitro demonstrated increased CCN3 protein. Transfecting CCN3 into BCR-ABL+ cells inhibited proliferation and decreased clonogenic potential. CCN3 plays an important role in internal and external cell-signaling pathways. Thus, BCR-ABL can regulate protein levels by governing secretion, a novel mechanism for this tyrosine kinase.

DNA sequence, structure, and tyrosine kinase activity of the Drosophila melanogaster Abelson proto-oncogene homolog

1988 ◽  
Vol 8 (2) ◽  
pp. 843-853
Author(s):  
M J Henkemeyer ◽  
R L Bennett ◽  
F B Gertler ◽  
F M Hoffmann
Keyword(s):  
Drosophila Melanogaster ◽  
Tyrosine Kinase ◽  
Dna Sequence ◽  
Kinase Activity ◽  
Essential Gene ◽  
Sequence Similarity ◽  
Homologous Region ◽  
Loss Of Function ◽  
Tyrosine Kinase Activity ◽  
Stage Of Development

We report our molecular characterization of the Drosophila melanogaster Abelson gene (abl), a gene in which recessive loss-of-function mutations result in lethality at the pupal stage of development. This essential gene consists of 10 exons extending over 26 kilobase pairs of genomic DNA. The DNA sequence encodes a protein of 1,520 amino acids with strong sequence similarity to the human c-abl proto-oncogene beginning in the type lb 5' exon and extending through the region essential for tyrosine kinase activity. When the tyrosine kinase homologous region was expressed in Escherichia coli, phosphorylation of proteins on tyrosine residues was observed with an antiphosphotyrosine antibody. These results show that the abl gene is highly conserved through evolution and encodes a functional tyrosine protein kinase required for Drosophila development.

scholarly journals Contributions of F-BAR and SH2 Domains of Fes Protein Tyrosine Kinase for Coupling to the FcεRI Pathway in Mast Cells

2008 ◽  
Vol 29 (2) ◽  
pp. 389-401 ◽  
Author(s):  
Victor A. McPherson ◽  
Stephanie Everingham ◽  
Robert Karisch ◽  
Julie A. Smith ◽  
Christian M. Udell ◽  
...  
Keyword(s):  
Mast Cells ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Regulatory Protein ◽  
Sh2 Domain ◽  
Wild Type ◽  
Protein Tyrosine ◽  
Bar Domain ◽  
Sh2 Domains

ABSTRACT This study investigates the roles of Fer-CIP4 homology (FCH)-Bin/amphiphysin/Rvs (F-BAR) and SH2 domains of Fes protein tyrosine kinase in regulating its activation and signaling downstream of the high-affinity immunoglobulin G (IgE) receptor (FcεRI) in mast cells. Homology modeling of the Fes F-BAR domain revealed conservation of some basic residues implicated in phosphoinositide binding (R113/K114). The Fes F-BAR can bind phosphoinositides and induce tubulation of liposomes in vitro. Mutation of R113/K114 to uncharged residues (RK/QQ) caused a significant reduction in phosphoinositide binding in vitro and a more diffuse cytoplasmic localization in transfected COS-7 cells. RBL-2H3 mast cells expressing full-length Fes carrying the RK/QQ mutation show defects in FcεRI-induced Fes tyrosine phosphorylation and degranulation compared to cells expressing wild-type Fes. This correlated with reduced localization to Lyn kinase-containing membrane fractions for the RK/QQ mutant compared to wild-type Fes in mast cells. The Fes SH2 domain also contributes to Fes signaling in mast cells, via interactions with the phosphorylated FcεRI β chain and the actin regulatory protein HS1. We show that Fes phosphorylates C-terminal tyrosine residues in HS1 implicated in actin stabilization. Thus, coordinated actions of the F-BAR and SH2 domains of Fes allow for coupling to FcεRI signaling and potential regulation the actin reorganization in mast cells.

Application of FASTTM Fragment-Based Lead Discovery and Structure-Guided Design to Discovery of Small Molecule Inhibitors of BCR-ABL Tyrosine Kinase Active Against the T315I Imatinib-Resistant Mutant.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 698-698 ◽  
Author(s):  
Stephen K. Burley
Keyword(s):  
Tyrosine Kinase ◽  
Fusion Gene ◽  
Clinical Success ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Lead Discovery ◽  
Abl Tyrosine Kinase ◽  
Imatinib Resistant

Abstract The Philadelphia chromosome translocation creates a BCR-ABL fusion gene that encodes a constitutively active BCR-ABL tyrosine kinase, which gives rise to chronic myelogenous leukemia (CML). The clinical success of imatinib (Gleevec) demonstrated that BCR-ABL tyrosine kinase inhibitors can provide effective treatment for CML. However, some CML patients treated with imatinib develop resistance leading to disease progression. The majority of resistance is due to point mutations in BCR-ABL, which give rise to active mutant enzymes that are insensitive to imatinib. In all, ~30 imatinib-resistant BCR-ABL mutants have been identified in clinical isolates. The T315I mutant represents ~20% of clinically observed mutations, making it one of the most common causes of resistance. Second-generation BCR-ABL inhibitors, including AMN-107 and BMS-354825, inhibit many of the clinically relevant mutants but not T315I. Mutant T315I BCR-ABL is, therefore, an important and challenging target for discovery of CML therapeutics. We have applied a proprietary X-ray crystallographic fragment-based lead discovery platform (FASTTM) and structure-guided lead optimization to identify potent inhibitors of wild-type BCR-ABL and the four most common mutants, including T315I. Our lead discovery efforts yielded five chemical series that inhibit both wild-type (WT) and T315I BCR-ABL. Compounds in our most advanced lead series potently inhibit proliferation of K562 cells and Ba/F3 cells with WT BCR-ABL and the four major clinically relevant BCR-ABL mutations (T315I, E255K, M351T, Y253F; see below). Further details describing in vitro and in vivo profiling of these novel BCR-ABL T315I inhibitors will be presented. Ba/F3 cell proliferation for BCR-ABL Inhibitors (EC50, nM) BCR-ABL Form Imatinib AMN-107 BMS-354825 SGX-70430 WT 790 33 12 11 T315I > 10000 > 10000 > 10000 21 Y253F 5700 370 8 334 E255K 8300 350 7 77 M351T 2000 38 28 15 Control Assay Ba/F3 (T315I) + IL3 > 10000 > 10000 > 10000 > 10000

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