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