Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase

Liedtke, Michaela; Pandey, Pramod; Kumar, Shailendra; Kharbanda, Surender; Küfe, Donald

doi:10.1038/sj.onc.1202117

Cited by 26 publications

(24 citation statements)

References 22 publications

(35 reference statements)

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“…However, we cannot exclude contributions of other parts of the SHP-1 protein, nor can we exclude the involvement of other proteins serving as linkers between BcrAbl and SHP-1 in mammalian cells (although there is a direct interaction in insect cells, see above). Similar results demonstrating an association between SHP-1 and p210 Bcr-Abl have been reported recently by Tauchi et al 25 and Liedtke et al 24 …”

Section: Shp-1 Is Part Of a Complex Containing Bcr-ablsupporting

confidence: 79%

“…21 Our results, together with those of Tauchi et al 25 and Liedtke et al 24 suggest that another PTP, SHP-1, also helps antagonize the effects of Bcr-Abl in hematopoietic cells. Together, these data suggest that inactivation of PTPs by genetic or epigenetic means may contribute to progression to blast crisis.…”

Section: Discussionsupporting

confidence: 58%

“…23 Two recent studies suggested that SHP-1 may also be present in a complex with Bcr-Abl. 24,25 SHP-1, a non-transmembrane PTP containing two N-terminal Src homology 2 (SH2) domains, is predominantly expressed in hematopoietic cells, where it is implicated in the negative regulation of signaling pathways mediated by growth factor, cytokine and antigen receptors. 3,26 While screening a large number of hematopoietic cell lines for SHP-1 expression, we found that K562 cells fail to express SHP-1 protein.…”

Section: Introductionmentioning

confidence: 99%

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Role of the tyrosine phosphatase SHP-1 in K562 cell differentiation

et al. 2001

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The erythro-megakaryoblastic leukemia cell line K562 undergoes erythroid or myeloid differentiation in response to treatment with various inducing agents. We observed that expression of the SH2-containing protein tyrosine phosphatase SHP-1 was induced upon exposure of K562 cells to differentiating agents. Under the same conditions, expression of SHP-2, a close relative of SHP-1, and the more distantly related PTP-1B remained unchanged. Induction of SHP-1 expression correlates with dephosphorylation of a specific and limited set of tyrosyl phosphoproteins, suggesting that dephosphorylation of these proteins may be important for the differentiation process. Importantly, expression of exogenous SHP-1 inhibits K562 proliferation and alters the adhesion properties of these cells, indicating a more differentiated phenotype. Moreover, SHP-1 is found in a complex with both p210 Bcr-Abl and p190 Bcr-Abl, suggesting that it may regulate Bcr-Abl or Bcr-Ablassociated phosphotyrosyl proteins. Our results indicate that induction of SHP-1 expression is important for K562 differentiation in response to various inducers and raise the possibility that functional inactivation of SHP-1 may play a role in progression to blast crisis in chronic myelogenous leukemia. Leukemia (2001) 15, 1424-1432.

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Section: Shp-1 Is Part Of a Complex Containing Bcr-ablsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

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Role of the tyrosine phosphatase SHP-1 in K562 cell differentiation

et al. 2001

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“…The involvement of SHP-1 in the PP2A-induced negative regulation of BCR/ABL kinase activity and expression is also supported by the fact that SHP-1 associates with BCR/ABL and its tyrosine phosphatase activity counteracts BCR/ABL leukaemogenic potential (Liedtke et al, 1998;Lim et al, 2000). Accordingly, expression of SHP-1 is diminished in most of leukaemias and lymphomas, SHP-1 downregulation leads to abnormal cell growth and SHP-1 activity is suppressed by different oncogenic tyrosine kinases (e.g.…”

Section: Adverse Molecular Effects Of Bcr/abl and Pp2amentioning

confidence: 84%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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“…Until now, the kinases and phosphatases responsible for phosphorylation/dephosphorylation of Tyr393 in vivo are not known, although a range of phosphatases influencing Bcr-Abl signalling have been described. [21][22][23][24] In vitro, the Hck tyrosine kinase, a member of the Src family, has been shown to phosphorylate Abl on Tyr393. 6 Most interestingly, a recent report describing that Src-kinases are overexpressed in imatinib-resistant patients which may lend further support to a possible role of Tyr393 in the development of resistance at least in some patients.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of tyrosine 393 in the kinase domain of Bcr-Abl influences the sensitivity towards imatinib in vivo

et al. 2003

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The Bcr-Abl fusion protein arising through the t(9;22)(q34;q11) reciprocal translocation is the causative agent in chronic myeloid leukemia and a subset of acute lymphocytic leukemia. Imatinib mesylate is a specific inhibitor of the Bcr-Abl kinase and has shown promising results in clinical studies. The structural relation between the Bcr-Abl oncogene and the tyrosine kinase inhibitor imatinib has recently been elucidated by an elegant crystal structure analysis, emphasizing the importance of dephosphorylated tyrosine 393 (Tyr393) in BcrAbl for access of the inhibitor to the kinase domain. By mutating this tyrosine to phenylalanine and thereby mimicking a constitutively dephosphorylated state, we now show that Ba/ F3 cells transformed by this mutant demonstrate an increased sensitivity towards imatinib in vivo. This effect is not due to an impaired kinase activity of Bcr-Abl Y393F, since a synthetic substrate is phosphorylated with similar kinetics. Treatment of Ba/F3 cells transfected with Bcr-Abl wild type with a phosphatase inhibitor diminished the effect of imatinib, but did not influence the growth of Ba/F3 cells transfected with BcrAblY393F. The results support the findings of the crystal structure and indicate that Tyr393 indeed plays a significant role for the sensitivity of Bcr-Abl towards imatinib in vivo. These data implicate the regulation of Tyr393 phosphorylation as a potential mechanism of imatinib resistance. Leukemia (2003) IntroductionThe tyrosine kinase inhibitor imatinib has recently emerged as an important new treatment option in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph + ) acute lymphocytic leukemias (ALL) carrying the t(9;22) translocation. 1,2 Unfortunately, many patients with advanced CML and nearly all patients with ALL quickly develop resistance to imatinib treatment. [3][4][5] Imatinib has been shown to bind specifically to the nucleotide-binding pocket in the catalytic domain of Bcr-Abl. 6 Tyrosine 393 (Tyr393) is located in the activation loop of the Bcr-Abl kinase domain and has been proposed to stabilize the activation loop in the open formation when phosphorylated, thereby restricting the access of imatinib to the catalytic region and compromising its inhibitory function. Thus, phosphorylation of Tyr393 may function as a switch, regulating accessibility of imatinib to its binding site in the Bcr-Abl protein. Therefore, other molecules that are able to 'flick the switch' may influence imatinib sensitivity in a Bcr-Abl tranformed cell, and overexpression of kinases or downregulation of phosphatases targeting Tyr393 may induce imatinib resistance. As the importance of this amino acid for imatinib binding has been shown in vitro, we aimed at examining the relevance of phosphorylation of Tyr393 in vivo. We demonstrate here that a mutant Bcr-Abl imitating a constitutively dephosphorylated Tyr393 renders Ba/F3 cells more sensitive towards imatinib inhibition. Materials and methods DNA constructs, cells and transfectionsThe mutation of Tyr3...

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Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase

Cited by 26 publications

References 22 publications

Role of the tyrosine phosphatase SHP-1 in K562 cell differentiation

Role of the tyrosine phosphatase SHP-1 in K562 cell differentiation

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Phosphorylation of tyrosine 393 in the kinase domain of Bcr-Abl influences the sensitivity towards imatinib in vivo

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