Elsevier

Cytokine

Volume 82, June 2016, Pages 52-57
Cytokine

TC-PTP and PTP1B: Regulating JAK–STAT signaling, controlling lymphoid malignancies

https://doi.org/10.1016/j.cyto.2015.12.025Get rights and content

Highlights

  • The JAK–STAT pathway is frequently mutated in leukemia and lymphoma.

  • STATs play a critical role in establishing a cell’s transcriptional program.

  • PTPs PTP1B and TC-PTP regulated JAK–STAT pathways.

  • PTP1B and TC-PTP mutations sequenced in leukemia and lymphoma.

  • Mutations results in elevated JAK–STAT signaling and changes in gene expression.

Abstract

Lymphoid malignancies are characterized by an accumulation of genetic lesions that act co-operatively to perturb signaling pathways and alter gene expression programs. The Janus kinases (JAK)–signal transducers and activators of transcription (STATs) pathway is one such pathway that is frequently mutated in leukemia and lymphoma. In response to cytokines and growth factors, a cascade of reversible tyrosine phosphorylation events propagates the JAK–STAT pathway from the cell surface to the nucleus. Activated STAT family members then play a fundamental role in establishing the transcriptional landscape of the cell. In leukemia and lymphoma, somatic mutations have been identified in JAK and STAT family members, as well as, negative regulators of the pathway. Most recently, inactivating mutations in the protein tyrosine phosphatase (PTP) genes PTPN1 (PTP1B) and PTPN2 (TC-PTP) were sequenced in B cell lymphoma and T cell acute lymphoblastic leukemia (T-ALL) respectively. The loss of PTP1B and TC-PTP phosphatase activity is associated with an increase in cytokine sensitivity, elevated JAK–STAT signaling, and changes in gene expression. As inactivation mutations in PTPN1 and PTPN2 are restricted to distinct subsets of leukemia and lymphoma, a future challenge will be to identify in which cellular contexts do they contributing to the initiation or maintenance of leukemogenesis or lymphomagenesis. As well, the molecular mechanisms by which PTP1B and TC-PTP loss co-operates with other genetic aberrations will need to be elucidated to design more effective therapeutic strategies.

Introduction

Lymphoid malignancies are diverse, categorized by structural genetic alterations and sequence mutations. Independently, these lesions are typically not sufficient for transformation but rather act co-operatively to promote leukemia or lymphoma.

Despite the wide range of genetic alterations associated with lymphoid malignancies, certain signaling pathways are repeatedly targeted. Cytogenetic and gene profiling strategies have identified recurrent alterations to transcription factor networks, antigen receptor signaling, cytokine receptor signaling and Ras signaling. In addition, to directly influencing cell proliferation, survival and metabolism, “re-wiring” of such signaling networks can initiate cell transformation by modifying gene expression programs.

Advancements in second-generation sequencing technology such as whole-genome, exome and transcriptome sequencing, have allowed for a more detailed characterization of the genomic landscapes of lymphoid malignancies [1]. Future challenges lie in linking perturbed signaling networks to changes in gene profiles. For example, failure to shut down the pre-thymic gene program in thymic progenitors blocks differentiation and promotes leukemogenesis [2]. Yet, the signaling pathways responsible for maintaining the pre-thymic gene program and consequently promoting lymphoid malignancies, remain ill-defined.

A signaling pathway deregulated in multiple lymphoid malignancy subtypes, is the Janus kinases (JAK)–signal transducers and activators of transcription (STATs) pathway. In leukemia and lymphoma, elevated phosphorylation of JAK and STAT molecules has been associated with pro-survival and drug resistance gene programs [3].

Protein tyrosine phosphorylation is a reversible post-translational modification controlled by protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP). Activating and deactivating mutations within PTK and PTP genes often result in enzymes which can either promote or suppress oncogenesis. The oncogenic capacity of dysregulated kinases has been discussed at length in previous reviews. Herein we focus on the emerging role of two phosphatases, PTP1B (gene PTPN1) and TC-PTP (gene PTPN2) in regulating JAK–STAT signaling in hematological diseases.

Section snippets

The JAK–STAT pathway

Intercellular communication contributes to immune cell homeostasis by regulating cell proliferation, differentiation, survival and metabolism. Cytokines are critical soluble mediators of such communication, activating signaling networks capable of promoting or suppressing gene expression. Within this network, the canonical JAK–STAT pathway is a direct link from cytokine receptors at the cell surface to the nucleus. Following binding of a cytokine to its cognate receptor, associated JAK

PTP1B

PTP1B is a classical NRPTP, composed of a N-terminal catalytic domain, two proline-rich motifs and a C-terminal hydrophobic region. The C-terminal hydrophobic domain anchors PTP1B to the cytoplasmic face of the endoplasmic reticulum (ER) where is has been shown to target a wide range of substrates including tyrosine kinases, adaptors, cytoskeleton protein and transcription factors [20]. Given the multitude of PTP1B substrates, it is not surprising that it has been implicated in diverse pathways

TC-PTP

The catalytic domain of the phosphatase TC-PTP is highly homologous to that of PTP1B and TC-PTP also contributes to the regulation of JAK–STAT signaling. It is therefore intriguing that the two enzymes are not interchangeable and each play unique roles immunity [34].

TC-PTP is an ubiquitously expressed NRPTP that exists as two splice variants. Both variants contain a N-terminal PTP domain following by a C-terminal domain that includes either a nuclear localization signaling (TC45) or a

Conclusion

Inactivating mutations of PTPN1 or PTPN2 have not been reported to drive leukemogenesis or lymphomagenesis independently. Rather, the loss of either PTP1B or TC-PTP has been shown to synergize with driver mutations. In the context of T-ALL, the loss of TC-PTP increases the oncogenic potential of NUP214-ABL1 and JAK1 and as a consequence, decrease inhibitor sensitivity [45], [47].

With the advancement of personalized targeted therapies, an evaluation of the expression level of TC-PTP may be a

Acknowledgements

We would like to thank Dr. N. Uetani for expert graphical assistance. This work was supported by grants awarded from the Leukemia and Lymphoma Society of Canada and the Canadian Cancer Society Research Institute. M.L.T is a holder of the Jeanne and Jean-Louis Lévesque Chair in Cancer Research.

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