PTP1B and TC-PTP: regulators of transformation and tumorigenesis

Stuible, Matthew; Doody, Karen M.; Tremblay, Michel L.

doi:10.1007/s10555-008-9115-1

Cited by 108 publications

(87 citation statements)

References 138 publications

(202 reference statements)

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“…To determine whether the observed cooperative effect was specific for JAK1 kinase, we performed an identical experiment with Ba/F3 cells ectopically expressing JAK2 wild-type, a sister kinase of JAK1, and no direct substrate of PTPN2. 23 We observed no transformation of JAK2 wild-type either alone or in combination with Ptpn2 shRNAmediated knockdown (Figure 2A). …”

Section: Jak1-overexpressing But Not Jak2-overexpressing Ba/f3 Cells mentioning

confidence: 89%

PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia

Kleppe

Soulier

Asnafi

et al. 2011

Blood

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We have recently reported inactivation of the tyrosine phosphatase PTPN2 (also known as TC-PTP) through deletion of the entire gene locus in ϳ 6% of T-cell acute lymphoblastic leukemia (T-ALL) cases. T-ALL is an aggressive disease of the thymocytes characterized by the stepwise accumulation of chromosomal abnormalities and gene mutations. In the present study, we confirmed the strong association of the PTPN2 deletion with TLX1 and NUP214-ABL1 expression. In addition, we found cooperation between PTPN2 deletion and activating JAK1 gene mutations. Activating mutations in JAK1 kinase occur in ϳ 10% of human T-ALL cases, and aberrant kinase activity has been shown to confer proliferation and survival advantages. Our results reveal that some JAK1 mutation-positive T- IntroductionT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia occurring in children and adults that is characterized by the massive production of undifferentiated thymocytes of clonal origin. T-ALL arises from the neoplastic transformation of a lymphoid progenitor cell that has accumulated multiple genetic lesions that alter its differentiation and self-renewal properties and provide proliferation and survival advantages. 1 The aberrant activation of transcription factors such as TAL1, TLX1, TLX3, MLL, and HOXA is thought to be the driving force of the transformation process and, based on the identity of the causal transcription factor, T-ALLs can be delineated in oncogenic subgroups with a characteristic immunophenotype and expression profile. 2,3 In addition to the ectopic expression of these transcription factors, several other lesions have been identified, including mutations of NOTCH1 and FBXW7, inactivation of PTEN, deletion of CDKN2A (p16), mutations of PHF6, and activation of LCK, JAK1, and ABL1 tyrosine kinases. [4][5][6][7][8][9][10][11][12] Mutations in JAK1 and episomal fusion of NUP214 to ABL1 are known oncogenic events that support the proliferation and survival of T-ALL cells. 9,10,13,14 Whereas the chimeric NUP214-ABL1 fusion gene occurs specifically in the cortical subtype characterized by aberrant expression of homeobox transcription factors TLX1 and TLX3, mutated JAK1 kinase appears in different T-ALL subgroups. Three independent studies have reported the occurrence of JAK1 mutations in T-ALL. In 2008, Flex et al studied a cohort of Italian T-ALL patients and found the frequency of JAK1 mutations in children and adults to be 2% and 18%, respectively. That study also found a clinical association with older age at diagnosis, poor treatment response, and overall predicted outcome. 10 Around the same time, a second group sequenced exons 5, 14, and 17 of JAK1 in 11 adult Korean T-ALL patients and identified 3 missense mutations in the coding region of JAK1 (27%). 14 However, the latest study performed by Asnafi et al could not confirm the frequencies reported previously. Sequence analysis of the JAK1 gene in 108 adult French T-ALL patients identified only 4 individuals with JAK1 mutations. 9 Whether JAK1 mutations occur...

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Section: Jak1-overexpressing But Not Jak2-overexpressing Ba/f3 Cells mentioning

confidence: 89%

PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia

Kleppe

Soulier

Asnafi

et al. 2011

Blood

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“…The PTP1B is considered to be a highly challenging drug target because of its highly conserved and positively charged active-site pocket 15 . Therefore, because of their selective affinity and relatively low IC 50 values of less than 1 mM, prodigiosin and its congeners provide a good starting point as potent drug candidates against type 2 diabetes mellitus and cancer 17 . PP2A, an enzyme belonging to the family of serine/threonine dephosphorylating phosphatases, was also investigated.…”

Section: Discussionmentioning

confidence: 99%

Effects of prodigiosin family compounds fromPseudoalteromonassp. 1020R on the activities of protein phosphatases and protein kinases

Soliev

Hosokawa

Enomoto

2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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Pseudoalteromonas sp. strain 1020R produces prodigiosin and its closely related congeners, which differ in the length of their alkyl side chains. These red-pigmented compounds were found to exhibit cytotoxicity against human leukemia cell lines. The compounds also showed dose-dependent inhibitory effects on protein phosphatase 2A and protein tyrosine phosphatase 1B (PTP1B), while remaining relatively inactive against protein kinases, including protein tyrosine kinase, Ca 2+ /calmodulin-dependent protein kinase and protein kinases A and C. Comparative studies of the individual pigmented compounds on PTP1B inhibition showed that as the chain length of the alkyl group at the C-3 position of the compound increased, the inhibitory effect on PTP1B decreased. These results suggest that protein phosphatases but not protein kinases might be involved in the cytotoxicity of the prodigiosin family of compounds against malignant cells.

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“…the insulin and IGF-1 receptors) as well as those that more readily undergo degradation after activation (e.g. the Met, EGF, and PDGF␤ receptors) (35). The complexity of the mode of action of PTP1B is underscored by the observation that its loss results in hyperphosphorylation of its RTK substrates and an increased susceptibility to B-cell lymphoma in a p53-null background on one hand (36) and delayed tumor formation in an ErbB2-induced mammary cancer mouse model on the other hand (37), suggesting a pleiotropic role for PTP1B in the maintenance of cellular homeostasis.…”

Section: Signaling Via Receptor Tyrosine Kinases (Rtks)mentioning

confidence: 99%

Protein-tyrosine Phosphatase 1B Modulates Early Endosome Fusion and Trafficking of Met and Epidermal Growth Factor Receptors

Sangwan

Abella

Lai

et al. 2011

Journal of Biological Chemistry

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Background:Signaling from RTKs is regulated at multiple levels; however, the role played by dephosphorylation in this process remains poorly understood. Results: We show that loss of PTP1B activity leads to abrogated receptor trafficking via the endocytic pathway. Conclusion: Dephosphorylation of the vesicle fusion machinery component NSF by PTP1B is required for RTK trafficking. Significance: This identifies a novel mechanism through which PTP1B can modulate RTK signaling.

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PTP1B and TC-PTP: regulators of transformation and tumorigenesis

Cited by 108 publications

References 138 publications

PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia

PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia

Effects of prodigiosin family compounds fromPseudoalteromonassp. 1020R on the activities of protein phosphatases and protein kinases

Protein-tyrosine Phosphatase 1B Modulates Early Endosome Fusion and Trafficking of Met and Epidermal Growth Factor Receptors

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