Protein tyrosine phosphatase PTP1B suppresses p210 bcr-abl-induced transformation of Rat-1 fibroblasts and promotes differentiation of K562 cells

LaMontagne, Kenneth R.; Hannon, Greg; Tonks, Nicholas K.

doi:10.1073/pnas.95.24.14094

Cited by 94 publications

(72 citation statements)

References 48 publications

(42 reference statements)

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“…Numerous studies have shown that Ras/ERK-and PI3-kinasedependent pathways are correlated with cell proliferation in various cells (Seger and Krebs, 1995;Toker and Cantley, 1997). Treatment with PTK inhibitors including herbimycin A, human a b l a n t i s e n s e oligonucleotide and CGP57148, a selective inhibitor of Bcr-Abl PTK ; C a r r o l l et al , 1997; D e i n i n g e r et al, 1997), leads to growth inhibition and induction of erythroid differentiation of K562 cells (Honma et al,1989;Honma et al, 1990;LaMontagne et al, 1998), indicating that the inhibition of Bcr-Abl PTK is an important step in induction of erythroid differentiation o f K562 cells. In the present study, it is shown that herbimycin A, r a s antisense oligonucleotide and PD98059 inhibited growth and ERK/MAPK activity of K562 cells and induced erythroid differentiation of K562 cells, whereas wortmannin inhibited growth of K562 cells, and neither inhibit ERK/AMAPK activity nor induce erythroid differentiation of K562 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of PTK activity by herbimycin A also resulted in the erythroid differentiation of K562 cells (Honma et al, 1989) and specific inhibition of abl PTK activity by human a b l antisense oligonucleotide and GP57148, a selective inhibitor of Bcr-Abl PTK Carroll et al, 1997), induces K562 cells into erythroid differentiation (Honma et al, 1990;LaMontagne et al, 1998). Therefore, inhibition of Bcr-Abl PTK appears to play an important role in the erythroid differentiation of K562 cells.…”

Section: Introductionmentioning

confidence: 99%

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Role of Ras/ERK-dependent pathway in the erythroid differentiation of K562 cells

Kang

Do²,

Kim³

et al. 1999

Exp Mol Med

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The chronic myelogenous leukemic K562 cell line carrying Bcr-Abl tyrosine kinase is considered as pluripotent hematopoietic progenitor cells expressing markers for erythroid, granulocytic, monocytic, and megakaryocytic lineages. Here we investigated the signaling modulations required for induction of erythroid differentiation of K562 cells. When the K562 cells were treated with herbimycin A (an inhibitor of protein tyrosine kinase), r a s antisense oligonucleotide, and PD98059 (a specific inhibitor of MEK), inhibition of ERK/MAPK activity and cell growth, and induction of erythroid differentiation were observed. The r a s mutant, pZIPRas 6 1 l e u -transfected cells, K562-Ras 6 1 l e u , have shown a markedly decreased cell proliferation rate with approximately 2-fold doubling time, compared with the parental K562 cells, and about 60% of these cells have shown the phenotype of erythroid differentiation. In addition, herbimycin A inhibited the growth rate and increased the erythroid differentiation, but did not affect the elevated activity of ERK/MAPK in the K562-Ras 61leu cells. On the other hand, effects of PD98059 on the growth and differentiation of K562-Ras 61leu cells were biphasic. At low concentration of PD98059, which inhibited the elevated activity of ERK/MAPK to the level of parental cells, the growth rate increased and the erythroid differentiation decreased slightly, and at high concentration of PD98059, which inhibited the elevated activity of ERK/MAPK below that of the parental cells, the growth rate turned down and the erythroid differentiation was restored to the untreated control level. Taken together, these results suggest that an appropriate activity of ERK/MAPK is required to maintain the rapid growth and transformed phenotype of K562 cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Ras/ERK-dependent pathway in the erythroid differentiation of K562 cells

Kang

Do²,

Kim³

et al. 1999

Exp Mol Med

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“…In fact, increased cytokine-independent clonogenic potential and inability of PP2A to promote BCR/ABL degradation was observed in BCR/ABL-transduced SHP-1-decifient CD34 þ /lineage-negative marrow myeloid progenitors cells . Interestingly, BCR/ABL dephosphorylation has been also observed in K562 cells overexpressing tyrosine phosphatase PTP1B (LaMontagne et al, 1998). Although ectopic PTP1B expression impairs clonogenicity and tumorigenesis of p210-BCR/ABL-transformed Rat-1 fibroblasts and induces K562 erythroid maturation (LaMontagne et al, 1998); it is still unclear why PTP1B expression is increased in BCR/ABL-expressing cells (LaMontagne et al, 1998) and whether PTP1B activity is altered in primary CML progenitors or changed during disease progression.…”

Section: Adverse Molecular Effects Of Bcr/abl and Pp2amentioning

confidence: 99%

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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“…For immortalization with simian virus 40 large T antigen, PTP1B Ϫ/Ϫ MEFs were infected with pZipTex (38), and these cells were maintained as a pool and used for subsequent experiments. WT human PTP1B (hPTP1B-WT) or the substrate-trapping mutant PTP1B-D181A (hPTP1B-D/A) (16) cloned into the retroviral vector pWZL (39,40) were the generous gifts of Dr. N. Tonks (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). To generate viral stocks, these vectors were transiently transfected into the Phoenix-Eco retroviral packaging line (http://www.stanford.edu/ group/nolan/index.html), and supernatants were collected 48 h later.…”

Section: Methodsmentioning

confidence: 99%

Regulation of Receptor Tyrosine Kinase Signaling by Protein Tyrosine Phosphatase-1B

Haj

Markova

Klaman

et al. 2003

Journal of Biological Chemistry

235

200

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Receptor tyrosine kinases (RTKs) are key regulators of cellular homeostasis. Based on in vitro and ex vivo studies, protein tyrosine phosphatase-1B (PTP1B) was implicated in the regulation of several RTKs, yet mice lacking PTP1B show defects mainly in insulin and leptin receptor signaling. To address this apparent paradox, we studied RTK signaling in primary and immortalized fibroblasts from PTP1B ؊/؊ mice. After growth factor treatment, cells lacking PTP1B exhibit increased and sustained phosphorylation of the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor (PDGFR). However, Erk activation is enhanced only slightly, and there is no increase in Akt activation in PTP1B-deficient cells. Our results show that PTP1B does play a role in regulating EGFR and PDGFR phosphorylation but that other signaling mechanisms can largely compensate for PTP1B deficiency. In-gel phosphatase experiments suggest that other PTPs may help to regulate the EGFR and PDGFR in PTP1Bfibroblasts. This and other compensatory mechanisms prevent widespread, uncontrolled activation of RTKs in the absence of PTP1B and probably explain the relatively mild effects of PTP1B deletion in mice.Regulation of cellular proliferation, adhesion, and migration is pivotal for maintaining homeostasis. Multiple peptide growth factors direct these processes to differing extents in primary fibroblasts and fibroblast cell lines. These growth factors signal via receptors with intrinsic protein-tyrosine kinase activity, termed receptor tyrosine kinases (RTKs).1 Ligand binding activates the intrinsic kinase activity of these receptors, resulting in the phosphorylation of multiple receptor tyrosyl residues. These serve as docking sites to recruit signal relay molecules containing src homology-2 and/or phosphotyrosine binding domains, most of which also are RTK substrates. Based largely on experiments in which wild-type PTPs or their catalytically impaired (dominant-negative) mutants were overexpressed, multiple PTPs, including LAR (7), DEP-1 (8), TC-PTP (9, 10), Shp-1 (11, 12), Shp-2 (13), and PTP1B (14 -17) have been implicated in the dephosphorylation of various RTKs. Which, if any, of these PTPs regulate RTK signaling under physiologically relevant conditions of expression has remained largely unclear. Also unknown is the extent to which RTK dephosphorylation, as opposed to other down-regulatory mechanisms such as RTK degradation and/or inhibitory seryl phosphorylation, plays the (a) key role in receptor inactivation.PTP1B is a widely expressed non-receptor PTP that is localized on intracellular membranes via a hydrophobic C-terminal targeting sequence (18,19). A role for PTP1B in the regulation of many cellular functions has been suggested, including integrin (20 -23), cadherin (24, 25), and cytokine receptor signaling (26 -28), cell cycle regulation (29 -31), and the response to cellular stress (32). Multiple studies indicated that PTP1B dephosphorylates the EGFR (16, 17) and the insulin receptor (IR) (14,(33)(34)(35). Analy...

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Protein tyrosine phosphatase PTP1B suppresses p210 bcr-abl-induced transformation of Rat-1 fibroblasts and promotes differentiation of K562 cells

Cited by 94 publications

References 48 publications

Role of Ras/ERK-dependent pathway in the erythroid differentiation of K562 cells

Role of Ras/ERK-dependent pathway in the erythroid differentiation of K562 cells

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

Regulation of Receptor Tyrosine Kinase Signaling by Protein Tyrosine Phosphatase-1B

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