BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias

1991 ◽  
Vol 11 (4) ◽  
pp. 1785-1792
Author(s):  
A J Muller ◽  
J C Young ◽  
A M Pendergast ◽  
M Pondel ◽  
N R Landau ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Transformation ◽  
Philadelphia Chromosome ◽  
Sh3 Domain ◽  
Kinase Domain ◽  
Chromosome Translocation ◽  
Regulatory Domains ◽  
Homology Region ◽  
Abl Tyrosine Kinase ◽  
Src Homology

The c-abl proto-oncogene encodes a cytoplasmic tyrosine kinase which is homologous to the src gene product in its kinase domain and in the upstream kinase regulatory domains SH2 (src homology region 2) and SH3 (src homology region 3). The murine v-abl oncogene product has lost the SH3 domain as a consequence of N-terminal fusion of gag sequences. Deletion of the SH3 domain is sufficient to render the murine c-abl proto-oncogene product transforming when myristylated N-terminal membrane localization sequences are also present. In contrast, the human BCR/ABL oncogene of the Philadelphia chromosome translocation has an intact SH3 domain and its product is not myristylated at the N terminus. To analyze the contribution of BCR-encoded sequences to BCR/ABL-mediated transformation, the effects of a series of deletions and substitutions were assessed in fibroblast and hematopoietic-cell transformation assays. BCR first-exon sequences specifically potentiate transformation and tyrosine kinase activation when they are fused to the second exon of otherwise intact c-ABL. This suggests that BCR-encoded sequences specifically interfere with negative regulation of the ABL-encoded tyrosine kinase, which would represent a novel mechanism for the activation of nonreceptor tyrosine kinase-encoding proto-oncogenes.

scholarly journals BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias.

1991 ◽  
Vol 11 (4) ◽  
pp. 1785-1792 ◽  
Author(s):  
A J Muller ◽  
J C Young ◽  
A M Pendergast ◽  
M Pondel ◽  
N R Landau ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Transformation ◽  
Philadelphia Chromosome ◽  
Sh3 Domain ◽  
Kinase Domain ◽  
Chromosome Translocation ◽  
Regulatory Domains ◽  
Homology Region ◽  
Abl Tyrosine Kinase ◽  
Src Homology

The c-abl proto-oncogene encodes a cytoplasmic tyrosine kinase which is homologous to the src gene product in its kinase domain and in the upstream kinase regulatory domains SH2 (src homology region 2) and SH3 (src homology region 3). The murine v-abl oncogene product has lost the SH3 domain as a consequence of N-terminal fusion of gag sequences. Deletion of the SH3 domain is sufficient to render the murine c-abl proto-oncogene product transforming when myristylated N-terminal membrane localization sequences are also present. In contrast, the human BCR/ABL oncogene of the Philadelphia chromosome translocation has an intact SH3 domain and its product is not myristylated at the N terminus. To analyze the contribution of BCR-encoded sequences to BCR/ABL-mediated transformation, the effects of a series of deletions and substitutions were assessed in fibroblast and hematopoietic-cell transformation assays. BCR first-exon sequences specifically potentiate transformation and tyrosine kinase activation when they are fused to the second exon of otherwise intact c-ABL. This suggests that BCR-encoded sequences specifically interfere with negative regulation of the ABL-encoded tyrosine kinase, which would represent a novel mechanism for the activation of nonreceptor tyrosine kinase-encoding proto-oncogenes.

scholarly journals The common src homology region 2 domain of cytoplasmic signaling proteins is a positive effector of v-fps tyrosine kinase function.

1989 ◽  
Vol 9 (10) ◽  
pp. 4131-4140 ◽  
Author(s):  
C A Koch ◽  
M Moran ◽  
I Sadowski ◽  
T Pawson
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Specific Activity ◽  
Intramolecular Interaction ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Homology Region ◽  
Src Homology ◽  
Type V

A conserved noncatalytic domain SH2 (for src homology region 2) is located immediately N terminal to the kinase domains of all cytoplasmic protein-tyrosine kinases. We found that the wild-type v-fps SH2 domain stimulated the enzymatic activity of the adjacent kinase domain 10-fold and functioned as a powerful positive effector of catalytic and transforming activities within the v-fps oncoprotein (P130gag-fps). Partial proteolysis of P130gag-fps and supporting genetic data indicated that the v-fps SH2 domain exerts its effect on catalytic activity through an intramolecular interaction with the kinase domain. Amino acid alterations in the SH2 domain that impaired kinase function interfered with association of the SH2 domain with the kinase domain. Deletion of a conserved octapeptide motif converted the v-fps SH2 domain from an activator to an inhibitor of tyrosine kinase activity. This latent inhibitory activity of v-fps SH2 has functional implications for phospholipase C-gamma and p21ras GTPase-activating protein, both of which have two distinct SH2 domains suggestive of complex regulation. In addition to regulating the specific activity of the kinase domain, the SH2 domain of P130gag-fps was also found to be required for the tyrosine phosphorylation of specific cellular proteins, notably polypeptides of 124 and 62 kilodaltons. The SH2 domain therefore appears to play a dual role in regulation of kinase activity and recognition of cellular substrates.

The common src homology region 2 domain of cytoplasmic signaling proteins is a positive effector of v-fps tyrosine kinase function

1989 ◽  
Vol 9 (10) ◽  
pp. 4131-4140
Author(s):  
C A Koch ◽  
M Moran ◽  
I Sadowski ◽  
T Pawson
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Specific Activity ◽  
Intramolecular Interaction ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Homology Region ◽  
Src Homology ◽  
Type V

A conserved noncatalytic domain SH2 (for src homology region 2) is located immediately N terminal to the kinase domains of all cytoplasmic protein-tyrosine kinases. We found that the wild-type v-fps SH2 domain stimulated the enzymatic activity of the adjacent kinase domain 10-fold and functioned as a powerful positive effector of catalytic and transforming activities within the v-fps oncoprotein (P130gag-fps). Partial proteolysis of P130gag-fps and supporting genetic data indicated that the v-fps SH2 domain exerts its effect on catalytic activity through an intramolecular interaction with the kinase domain. Amino acid alterations in the SH2 domain that impaired kinase function interfered with association of the SH2 domain with the kinase domain. Deletion of a conserved octapeptide motif converted the v-fps SH2 domain from an activator to an inhibitor of tyrosine kinase activity. This latent inhibitory activity of v-fps SH2 has functional implications for phospholipase C-gamma and p21ras GTPase-activating protein, both of which have two distinct SH2 domains suggestive of complex regulation. In addition to regulating the specific activity of the kinase domain, the SH2 domain of P130gag-fps was also found to be required for the tyrosine phosphorylation of specific cellular proteins, notably polypeptides of 124 and 62 kilodaltons. The SH2 domain therefore appears to play a dual role in regulation of kinase activity and recognition of cellular substrates.

scholarly journals Mutations Associated with Imatinib Mesylate Resistance - Review

Folia Medica ◽  
2018 ◽  
Vol 60 (4) ◽  
pp. 617-623 ◽  
Author(s):  
Alexandar J. Linev ◽  
Hristo J. Ivanov ◽  
Ivan G. Zhelyazkov ◽  
Hristina Ivanova ◽  
Veselina S. Goranova-Marinova ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
Kinase Domain ◽  
Chromosome Translocation ◽  
New Drugs ◽  
Chromosome 22Q11.2

Abstract Chronic myeloid leukemia (CML) arises from the fusion of the BCR and the ABL1 genes. The BCR gene (chromosome 22q11.2) and the ABL1 gene (chromosome 9q34) fuse together due to reciprocal chromosome translocation forming the Philadelphia chromosome (Ph). This fusion gene codes tyrosine kinase which accelerates the cell division and reduces DNA repair. Imatinib mesylate is a selective inhibitor of this tyrosine kinase. It is the first-line treatment for CML-patients. However, it became clear that Philadelphia-positive (Ph+) cells could evolve to elude inhibition due to point mutations within the BCR-ABL kinase domain. To date more than 40 mutations have been identified and their early detection is important for clinical treatment. With the development of the new tyrosine kinase inhibitors (TKIs), associated with these mutations, the resistance problem seems to diminish, as some of the new drugs are less prone to resistance. The aim of this review is to focus on the diff erent mutations leading to resistance.

scholarly journals ANKRD54 preferentially selects Bruton’s Tyrosine Kinase (BTK) from a Human Src-Homology 3 (SH3) domain library

PLoS ONE ◽  
2017 ◽  
Vol 12 (4) ◽  
pp. e0174909 ◽  
Author(s):  
Manuela O. Gustafsson ◽  
Dara K. Mohammad ◽  
Erkko Ylösmäki ◽  
Hyunseok Choi ◽  
Subhash Shrestha ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Sh3 Domain ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Src Homology 3 ◽  
Src Homology

scholarly journals Inhibition of VRAC by c-Src tyrosine kinase targeted to caveolae is mediated by the Src homology domains

2001 ◽  
Vol 281 (1) ◽  
pp. C248-C256 ◽  
Author(s):  
Dominique Trouet ◽  
Iris Carton ◽  
Diane Hermans ◽  
Guy Droogmans ◽  
Bernd Nilius ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Inhibitory Effect ◽  
Kinase Domain ◽  
Wild Type ◽  
Patch Clamp Technique ◽  
Src Tyrosine Kinase ◽  
Src Homology ◽  
Cpae Cells ◽  
Src Homology Domains ◽  
Homology Domains

We used the whole cell patch-clamp technique in calf pulmonary endothelial (CPAE) cells to investigate the effect of wild-type and mutant c-Src tyrosine kinase on I Cl,swell, the swelling-induced Cl−current through volume-regulated anion channels (VRAC). Transient transfection of wild-type c-Src in CPAE cells did not significantly affect I Cl,swell. However, transfection of c-Src with a Ser3Cys mutation that introduces a dual acylation signal and targets c-Src to lipid rafts and caveolae strongly repressed hypotonicity-induced I Cl,swell in CPAE cells. Kinase activity was dispensable for the inhibition of I Cl,swell, since kinase-deficient c-Src Ser3Cys either with an inactivating point mutation in the kinase domain or with the entire kinase domain deleted still suppressed VRAC activity. Again, the Ser3Cys mutation was required to obtain maximal inhibition by the kinase-deleted c-Src. In contrast, the inhibitory effect was completely lost when the Src homology domains 2 and 3 were deleted in c-Src. We therefore conclude that c-Src-mediated inhibition of VRAC requires compartmentalization of c-Src to caveolae and that the Src homology domains 2 and/or 3 are necessary and sufficient for inhibition.

scholarly journals New Heteroleptic Ruthenium(II) Complexes with Sulfamethoxypyridazine and Diimines as Potential Antitumor Agents

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2154
Author(s):  
Ariane C.C. de Melo ◽  
Jaime M.S.V.P. Santana ◽  
Kelen J.R.C. Nunes ◽  
Bernardo L. Rodrigues ◽  
Nathalia Castilho ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Antitumor Agents ◽  
Sh3 Domain ◽  
Myelogenous Leukemia ◽  
Distorted Octahedral Geometry ◽  
Ionization Mass ◽  
Nmr Studies ◽  
Abl Tyrosine Kinase ◽  
Mixed Ligands ◽  
Src Homology

Two new complexes of Ru(II) with mixed ligands were prepared: [Ru(bpy)2smp](PF6) (1) and [Ru(phen)2smp](PF6) (2), in which smp = sulfamethoxypyridazine; bpy = 2,2′-bipyridine; phen = 1,10-phenanthroline. The complexes have been characterized by elemental and conductivity analyses; infrared, NMR, and electrospray ionization mass spectroscopies; and X-ray diffraction of single crystal. Structural analyses reveal a distorted octahedral geometry around Ru(II) that is bound to two bpy (in 1) or two phen (in 2) via their two heterocyclic nitrogens and to two nitrogen atoms from sulfamethoxypyridazine—one of the methoxypyridazine ring and the sulfonamidic nitrogen, which is deprotonated. Both complexes inhibit the growth of chronic myelogenous leukemia cells. The interaction of the complexes with bovine serum albumin and DNA is described. DNA footprinting using an oligonucleotide as substrate showed the complexes’ preference for thymine base rich sites. It is worth notifying that the complexes interact with the Src homology SH3 domain of the Abl tyrosine kinase protein. Abl protein is involved in signal transduction and implicated in the development of chronic myelogenous leukemia. Nuclear magnetic resonance (NMR) studies of the interaction of complex 2 with the Abl-SH3 domain showed that the most affected residues were T79, G97, W99, and Y115.

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