Requirement of two specific tyrosine residues for the catalytic activity of Bcr serine/threonine kinase

Wu, Yun; Liu, Jiaxin; Arlinghaus, Ralph B.

doi:10.1038/sj.onc.1201524

Cited by 22 publications

(31 citation statements)

References 10 publications

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“…Peptide mapping studies of site-directed mutants of Bcr-Abl when compared to wild-type Bcr-Abl suggested that tyrosine residues (Y) 177, Y283, Y328 and Y360 are sites of tyrosine phosphorylation resulting from Bcr-Abl autophosphorylation (Pendergast et al, 1993;Puil et al, 1994;Liu et al, 1996b;Wu et al, 1998). In agreement with our earlier findings , all of these sites are located within the first exon coding sequence of the BCR gene.…”

Section: Bcr-abl Autophosphorylates At Sites Encoded By the First Exosupporting

confidence: 79%

“…The Bcr protein co-expressed with BcrAbl is phosphorylated at these sites just as in the cis Bcr sequences within the Bcr-Abl oncoprotein, itself Liu et al, 1996b;Wu et al, 1998). Besides pTyr sites mentioned above, additional sites of Bcr tyrosine phosphorylation undoubtedly exist but have not yet been identified.…”

Section: Bcr-abl Autophosphorylates At Sites Encoded By the First Exomentioning

confidence: 99%

“…Similarly, the Y328F mutant also curtailed Bcr transkinase activity, but this mutation also reduced the ability of Bcr to autophosphorylate on serine residues. The double mutant Y328F/Y360F blocked both the trans-and autokinase activities of the Bcr protein (Wu et al, 1998). A model was proposed indicating that the hydroxyl groups of tyrosine 328 and 360 are critically involved in regulating Bcr's serine/threonine kinase activity ( Figure 1) (Arlinghaus, 1998).…”

Section: Activation Of the Ras Pathwaymentioning

confidence: 99%

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Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia

Arlinghaus

2002

Oncogene

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The fusion of 5' parts of the BCR gene to the ABL gene at the second exon yields several forms of an oncogenic Bcr-Abl oncoprotein observed in several types of Philadelphia chromosome positive leukemia patients. The first exon of the BCR gene is a critical part of this fusion, as the coiled-coil domain at the amino terminal domain of the Bcr protein causes oligomerization of the Bcr-Abl oncoprotein forming tetramers, thereby activating the tyrosine kinase activity of the normally silent c-Abl protein. Another consequence of this Bcr-Abl fusion is the extensive autophosphorylation of the cis Bcr protein sequences on tyrosine residues. This review will summarize the effects of Bcr-Abl autophosphorylation on tyrosines as they relate to the oncogenic activity of Bcr-Abl, and as a means to inactivate the serine/threonine kinase activity of the Bcr protein. The review also discusses our findings that show that phosphoserine Bcr by means of a unique structure, binds to the Abl SH2 domain of the Bcr-Abl oncoprotein, and as a result this SH2 binding inhibits the oncogenic effects of the oncoprotein. Our results indicate that one effect of this binding is inhibition of the Bcr-Abl tyrosine kinase. Serine 354 of Bcr plays a major role in this inhibition. In the case of Bcr(64-413), serine 354 is required for the formation of the unique Bcr structure that binds to the Abl SH2 domain.

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Section: Bcr-abl Autophosphorylates At Sites Encoded By the First Exosupporting

confidence: 79%

Section: Bcr-abl Autophosphorylates At Sites Encoded By the First Exomentioning

confidence: 99%

Section: Activation Of the Ras Pathwaymentioning

confidence: 99%

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Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia

Arlinghaus

2002

Oncogene

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“…In this regard Bcr sequences activate the tyrosine kinase function of Bcr-Abl McWhirter and Wang, 1991), and Bcr tyrosine 177 when phosphorylated binds Grb2, an activator of the Ras pathway (Pendergast et al, 1993;Puil et al, 1994). Recently, we have demonstrated that tyrosine residues 328 and 360 within the ®rst exon of the Bcr protein are critically involved in regulating Bcr's serine/threonine kinase activity (Liu et al, 1996b;Wu et al, 1998). Moreover, tyrosine phosphorylation of Bcr ®rst exon sequences inhibits Bcr's serine/threonine protein kinase activity, probably as a direct result of the phosphorylation of these two tyrosine residues (Liu et al, 1996b;Wu et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we have demonstrated that tyrosine residues 328 and 360 within the ®rst exon of the Bcr protein are critically involved in regulating Bcr's serine/threonine kinase activity (Liu et al, 1996b;Wu et al, 1998). Moreover, tyrosine phosphorylation of Bcr ®rst exon sequences inhibits Bcr's serine/threonine protein kinase activity, probably as a direct result of the phosphorylation of these two tyrosine residues (Liu et al, 1996b;Wu et al, 1998). Given the inhibitory eects of BcrAbl on the kinase activity of Bcr, we searched for eects of the Bcr protein on the tyrosine kinase activity of Bcr-Abl and its resultant oncogenic activity.…”

Section: Introductionmentioning

confidence: 99%

Bcr: a negative regulator of the Bcr-Abl oncoprotein

Dai

et al. 1999

Oncogene

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Chronic myelogenous leukemia is typically characterized by the presence of the Philadelphia chromosome (Ph) in which 5' portions of the BCR gene are fused to a large portion of the ABL gene. Our studies and those of others indicate that Bcr sequences within the Bcr-Abl oncoprotein are critically involved in activating the Abl tyrosine kinase and actively participate in the oncogenic response, which is generated by the Bcr-Abl oncoprotein. We investigated the role of the Bcr protein in the oncogenic eects of Bcr-Abl. Reduction of the level of the Bcr protein by incubating cells with a 3' BCR anti-sense oligodeoxynucleotide increased the growth rate and survival of hematopoietic cell lines expressing Bcr-Abl. Also, enforced expression of Bcr in Bcr-Abl cell lines strongly reduced transformation eciency. Induction of Bcr expression drastically reduced the phosphotyrosine content of Bcr-Abl in Rat-1 ®broblasts transformed by P185 BCR-ABL and in hematopoietic cells expressing P210 Bcr-Abl within days following induction of Bcr. Rat-1/P185 cells maintained for three weeks after Bcr induction had dramatically reduced amounts of phosphotyrosine proteins compared to cells in which Bcr expression was repressed by the addition of Tet. In contrast Bcr expression did not decrease the phosphotyrosine content of either v-Src or activated Neu tyrosine kinase. Importantly, the phosphotyrosine content of total P160 BCR (induced plus endogenous) was strongly reduced by inducing expression of Bcr, indicating that the induced Bcr protein was not a target of the tyrosine kinase activity of Bcr-Abl but instead functioned as an inhibitor of Bcr-Abl. These results show that the Bcr protein can function as a negative regulator of Bcr-Abl, but that the inhibitory eects of Bcr are dependent on achieving an elevated level of Bcr expression relative to Bcr-Abl.

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Preparation and Application of Polyclonal and Monoclonal Sequence‐Specific Anti‐Phosphoamino Acid Antibodies

Arlinghaus

2003

CP Protein Science

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This unit discusses the issues that must be considered in the design, production, and characterization of polyclonal and monoclonal sequence-specific anti-phosphoamino acid antibodies. Protocols are provided for generating and purifying such antibodies, and methods are also provided for producing useful polyclonal antibodies in a non-purified form. Support protocols describe coupling of peptides or phosphotyrosine to a solid support for use in affinity chromatography. An example of the generation, purification, and characterization of two sequence-specific anti-phosphopeptide antibodies specific for different sequences of a single phosphoprotein is described. The cross-reactivity of such antibodies, which is a common problem with anti-peptide antibodies, is also discussed.

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Requirement of two specific tyrosine residues for the catalytic activity of Bcr serine/threonine kinase

Cited by 22 publications

References 10 publications

Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia

Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia

Bcr: a negative regulator of the Bcr-Abl oncoprotein

Preparation and Application of Polyclonal and Monoclonal Sequence‐Specific Anti‐Phosphoamino Acid Antibodies

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