Roles of JAK2 in Aging, Inflammation, Hematopoiesis and Malignant Transformation

Clonal alterations in hematopoietic cells occur during aging and are often associated with the establishment of a subclinical inflammatory environment. Several age-related conditions and diseases may be initiated or promoted by these alterations. JAK2 mutations are among the most frequently mutated genes in blood cells during aging. The most common mutation within the JAK2 gene is JAK2-V617F that leads to constitutive activation of the kinase and thereby aberrant engagement of downstream signaling pathways. JAK2 mutations can act as central drivers of myeloproliferative neoplasia, a pre-leukemic and age-related malignancy. Likewise, hyperactive JAK-signaling is a hallmark of immune diseases and critically influences inflammation, coagulation and thrombosis. In this review we aim to summarize the current knowledge on JAK2 in clonal hematopoiesis during aging, the role of JAK-signaling in inflammation and lymphocyte biology and JAK2 function in age-related diseases and malignant transformation.

Download Full-text

Molecular Mechanisms of JAK2V617F Oncogenic Activation: The JAK2- V617F Mutant Utilizes the SH2 Domain for Constitutive Kinase Activity in the Presence of Unstimulated Heterodimeric Cytokine Receptor.

Blood ◽

10.1182/blood.v112.11.175.175 ◽

2008 ◽

Vol 112 (11) ◽

pp. 175-175

Author(s):

Sivahari P Gorantla ◽

Tobias Dechow ◽

Rebekka Grundler ◽

Christian Peschel ◽

Justus Duyster

Keyword(s):

Molecular Mechanisms ◽

Kinase Activity ◽

Jak2 V617f ◽

Sh2 Domain ◽

Cytokine Receptor ◽

Cytokine Receptors ◽

Type I ◽

Constitutive Activation ◽

Downstream Signaling

Abstract The JAK2-V617F mutation has been reported in the majority of MPDs including PV, ET, and IMF. This mutation leads to the constitutive activation of the JAK2 tyrosine kinase activity and overexpression of JAK2V617F renders hematopoietic cell lines growth factor-independent. However, the molecular mechanism leading to constitutive activation of JAK2V617F is largely unclear and the requirement of homodimeric or heterodimeric cytokine receptors needs to be determined. Here we show that oncogenic JAK2-V617F requires an intact SH2 domain for constitutive kinase activity. To this end we mutated the conserved arginine 426 within the SH2 domain to a lysine. Ba/F3 cells expressing JAK2V617F grew IL-3-independent and showed constitutive activation of JAK2, STAT5, and ERK1/2. In contrast, introduction of the SH2 mutation in JAK2V617F abrogated both transformation as well as constitutive activation of downstream signaling pathways. Accordingly, reconstitution of JAK2 mutants in a JAK2-negative cell line with IL-3R co-expression revealed reduced activation of JAK2 when the SH2 domain was mutated. It has been reported that JAK2 binding to homodimeric type I cytokine receptor may facilitate JAK2V617F-mediated transformation. Interestingly, co-expression of the homodomeric EpoR with SH2 mutated JAK2V617F rescues the phenotype indicating that the SH2 domain is required for JAK2 signaling in the presence of heterodimeric but not homodimeric cytokine receptors. Membrane localization studies showed equal membrane distribution of SH2-mutated and unmutated JAK2-V617F indicating that the SH2 domain mutation does not affect subcellular distribution of JAK2. However, co-IP experiments revealed a possible role for the SH2 domain in the dimerization and transphosphorylation of JAK2. Consequently, reduced transphosphorylation was seen in IL-3R- but not in EpoR-expressing cells. In a BM transplantation model we found that an intact SH2 domain in JAK2V617F was required for the induction of a MPD-like disease. Thus, our results points to an important role of the SH2 domain for the constitutive activation of JAK2V617F in cells expressing heterodimeric cytokine receptors.

Download Full-text

The Jak2 V617F Oncogene Associated with Polycythemia Vera Requires a Functional FERM Domain for Transformation and for Expression of the Myc and Pim Proto-Oncogenes.

Blood ◽

10.1182/blood.v108.11.3611.3611 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3611-3611

Author(s):

Martin Sattler ◽

Brian J. Crowley ◽

Jeffrey R. Gonneville ◽

Jeremy Ho ◽

Heidi H. Hudon ◽

...

Keyword(s):

Growth Factor ◽

Polycythemia Vera ◽

Point Mutation ◽

Hematopoietic Cells ◽

Growth Factor Receptor ◽

Jak2 V617f ◽

Ferm Domain ◽

Constitutive Activation ◽

Epo Receptor

Abstract The V617F activating point mutation in Jak2 has been shown to be associated with a proportion of patients with myeloproliferative disorders, including polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. In normal hematopoietic cells, Jak2 signals only when associated with a growth factor receptor (such as the Epo receptor), but the role of receptors in transformation by Jak2V617F has been controversial. Constructs expressing wild type or Jak2V617F, with and without a point mutation in the FERM domain (Y114A) required for receptor binding, were introduced into BaF3 cells already expressing a human Epo receptor. These cells were then evaluated for growth factor independence, response to growth factors, and activation of several critical Jak2 signaling pathways. We found that, whereas BaF3-EpoR cells are readily transformed by Jak2V617F to Epo-independence, the addition of the FERM domain mutation blocked transformation to factor independence. Also, the FERM domain was required for induction of reactive oxygen species by Jak2V617F. Further, while cells expressing Jak2V617F had constitutive activation of STAT5, cells expressing Jak2 V617F/Y114A did not, suggesting that signaling is defective at a very proximal level. In addition, Jak2V617F induced expression of the Myc and Pim proto-oncogenes, which are known to cooperate in the transformation of hematopoietic cells. The expression of both proteins was dependent on a functional FERM domain. Finally, we evaluated the role of active STAT5 in transformation of BaF3 cells by introducing a STAT5 mutant that is constitutively activated, and found that activation of STAT5, by itself, was sufficient to induce Jak2V617F-dependent downstream targets believed to be critical for transformation, including Myc and Pim. Overall, our results suggest that constitutive activation of Jak2 requires an intact FERM domain for a transforming phenotype, and is necessary for activation of the major target of Jak2, STAT5. These results also suggest that small molecules that target Jak2, the FERM domain, or STAT5 would have activity in diseases associated with V617F mutations.

Download Full-text

Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

Biological Chemistry ◽

10.1515/hsz-2016-0216 ◽

2016 ◽

Vol 397 (12) ◽

pp. 1315-1333 ◽

Cited By ~ 28

Author(s):

Isabel Meininger ◽

Daniel Krappmann

Keyword(s):

Current Knowledge ◽

Inflammatory Diseases ◽

Critical Role ◽

Antigen Receptor ◽

Lymphocyte Activation ◽

Downstream Signaling ◽

Antigen Receptor Signaling ◽

Autoimmune And Inflammatory Diseases ◽

And Function

Abstract The CARMA1-BCL10-MALT1 (CBM) signalosome triggers canonical NF-κB signaling and lymphocyte activation upon antigen-receptor stimulation. Genetic studies in mice and the analysis of human immune pathologies unveiled a critical role of the CBM complex in adaptive immune responses. Great progress has been made in elucidating the fundamental mechanisms that dictate CBM assembly and disassembly. By bridging proximal antigen-receptor signaling to downstream signaling pathways, the CBM complex exerts a crucial scaffolding function. Moreover, the MALT1 subunit confers a unique proteolytic activity that is key for lymphocyte activation. Deregulated ‘chronic’ CBM signaling drives constitutive NF-κB signaling and MALT1 activation, which contribute to the development of autoimmune and inflammatory diseases as well as lymphomagenesis. Thus, the processes that govern CBM activation and function are promising targets for the treatment of immune disorders. Here, we summarize the current knowledge on the functions and mechanisms of CBM signaling in lymphocytes and how CBM deregulations contribute to aberrant signaling in malignant lymphomas.

Download Full-text

Oncogenic JAK2V617F requires an intact SH2-like domain for constitutive activation and induction of a myeloproliferative disease in mice

Blood ◽

10.1182/blood-2009-07-236133 ◽

2010 ◽

Vol 116 (22) ◽

pp. 4600-4611 ◽

Cited By ~ 15

Author(s):

Sivahari P. Gorantla ◽

Tobias N. Dechow ◽

Rebekka Grundler ◽

Anna Lena Illert ◽

Christian Meyer zum Büschenfelde ◽

...

Keyword(s):

Myeloproliferative Neoplasms ◽

Critical Role ◽

Sh2 Domain ◽

Receptor Expression ◽

Cytokine Receptor ◽

Myeloproliferative Disease ◽

Constitutive Activation ◽

Downstream Signaling ◽

Strict Requirement

Abstract The oncogenic JAK2V617F mutation is found in myeloproliferative neoplasms (MPNs) and is believed to be critical for leukemogenesis. Here we show that JAK2V617F requires an intact SH2 domain for constitutive activation of downstream signaling pathways. In addition, there is a strict requirement of cytokine receptor expression for the activation of this oncogene. Further analysis showed that the SH2 domain mutation did not interfere with JAK2 membrane distribution. However, coimmunoprecipitated experiments revealed a role for the SH2 domain in the aggregation and cross-phosphorylation of JAK2V617F at the cell membrane. Forced overexpression of cytokine receptors could rescue the JAK2V617F SH2 mutant supporting a critical role of JAK2V617F abundance for constitutive activation. However, under physiologic cytokine receptor expression the SH2 domain is absolutely necessary for oncogenic JAK2V617F activation. This is demonstrated in a bone marrow transplantation model, in which an intact SH2 domain in JAK2V617F is required for the induction of an MPN-like disease. Thus, our results points to an indispensable role of the SH2 domain in JAK2V617F-induced MPNs.

Download Full-text

Transcription Factors Associated With IL-15 Cytokine Signaling During NK Cell Development

Frontiers in Immunology ◽

10.3389/fimmu.2021.610789 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiang Wang ◽

Xiang-Yu Zhao

Keyword(s):

Nk Cells ◽

Developmental Stages ◽

Nk Cell ◽

Current Knowledge ◽

Cell Development ◽

Cytokine Signaling ◽

Hematopoietic Stem ◽

Downstream Signaling ◽

Downstream Target

Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and possess important functional properties in anti-viral and anti-tumor responses; thus, these cells have broad potential for clinical utilization. NK cells originate from hematopoietic stem cells (HSCs) through the following two independent and continuous processes: early commitment from HSCs to IL-15-responsive NK cell progenitors (NKPs) and subsequent differentiation into mature NK cells in response to IL-15. IL-15 is the most important cytokine for NK cell development, is produced by both hematopoietic and nonhematopoietic cells, and functions through a distinct delivery process termed transpresentation. Upon being transpresented to NK cells, IL-15 contributes to NK cell development via the activation of several downstream signaling pathways, including the Ras–MEK–MAPK, JAK–STAT5, and PI3K–ATK–mTOR pathways. Nonetheless, the exact role of IL-15 in NK cell development has not been discussed in a consecutive and comprehensive manner. Here, we review current knowledge about the indispensable role of IL-15 in NK cell development and address which cells produce IL-15 to support NK cell development and when IL-15 exerts its function during multiple developmental stages. Specifically, we highlight how IL-15 supports NK cell development by elucidating the distinct transpresentation of IL-15 to NK cells and revealing the downstream target of IL-15 signaling during NK cell development.

Download Full-text

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

Molecular Cancer ◽

10.1186/s12943-021-01441-4 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Gongmin Zhu ◽

Lijiao Pei ◽

Hongwei Xia ◽

Qiulin Tang ◽

Feng Bi

Keyword(s):

Colorectal Cancer ◽

Routine Clinical Practice ◽

Diagnosis And Treatment ◽

Constitutive Activation ◽

Downstream Signaling ◽

Dismal Prognosis ◽

Allele Specific ◽

Kras Protein ◽

Specific Inhibitors

AbstractColorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.

Download Full-text

Can diagnostic imaging help improve elder abuse detection?

British Journal of Radiology ◽

10.1259/bjr.20190632 ◽

2020 ◽

Vol 93 (1110) ◽

pp. 20190632

Author(s):

Taryn J Rohringer ◽

Tony E Rosen ◽

Mihan R Lee ◽

Pallavi Sagar ◽

Kieran J Murphy

Keyword(s):

Diagnostic Imaging ◽

Elder Abuse ◽

Current Knowledge ◽

Critical Role ◽

Systematic Research ◽

Imaging Findings ◽

Clinical Workflow ◽

Age Related ◽

Patterns Of Injury

Elder abuse is an underdetected, under-reported issue with severe consequences. Its detection presents unique challenges based on characteristics of this vulnerable population, including cognitive impairment, age-related deconditioning, and an increased number of co-morbidities, all of which predispose to increase vulnerability to injury. While radiologists play a critical role in detection of child abuse, this role is currently not paralleled in detection of elder abuse. We conducted a thorough review of the literature using MEDLINE to describe the current knowledge on injury patterns and injury findings seen in elder abuse, as well as barriers to and recommendations for an increased role of diagnostic imaging in elder abuse detection. Barriers limiting the role of radiologists include lack of training and paucity of rigorous systematic research delineating distinctive imaging findings for physical elder abuse. We outline the current ways in which imaging can help raise clinical suspicion for elder abuse, including inconsistencies between purported mechanism of injury and imaging findings, injury location, multiple injuries at differing stages of healing, and particular patterns of injury likely to be intentionally inflicted. We additionally outline the mechanism by which medical education and clinical workflow may be modified to increase the role for imaging and radiologist participation in detecting abuse in older adult patients, and identify potential future directions for further systematic research.

Download Full-text

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00936.2012 ◽

2013 ◽

Vol 305 (4) ◽

pp. H459-H476 ◽

Cited By ~ 111

Author(s):

Emanuele Marzetti ◽

Anna Csiszar ◽

Debapriya Dutta ◽

Gauthami Balagopal ◽

Riccardo Calvani ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Cardiovascular System ◽

Current Knowledge ◽

Mitochondrial Dynamics ◽

Late Life ◽

Age Related ◽

Functional Consequences ◽

Cardiovascular Aging ◽

The Life Course

Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The age-related accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD.

Download Full-text

Mitochondria, immunosenescence and inflammaging: a role for mitokines?

Seminars in Immunopathology ◽

10.1007/s00281-020-00813-0 ◽

2020 ◽

Vol 42 (5) ◽

pp. 607-617 ◽

Cited By ~ 4

Author(s):

Maria Conte ◽

Morena Martucci ◽

Antonio Chiariello ◽

Claudio Franceschi ◽

Stefano Salvioli

Keyword(s):

Immune Responses ◽

Acute Inflammation ◽

Current Knowledge ◽

Low Grade ◽

Mitochondrial Stress ◽

Age Related ◽

Metabolic Mechanism ◽

Anti Inflammatory ◽

Low Grade Inflammation

AbstractA global reshaping of the immune responses occurs with ageing, indicated as immunosenescence, where mitochondria and mitochondrial metabolism play an important role. However, much less is known about the role of mitochondrial stress response in this reshaping and in particular of the molecules induced by such response, collectively indicated as mitokines. In this review, we summarize the current knowledge on the role of mitokines in modulating immune response and inflammation focusing on GDF15, FGF21 and humanin and their possible involvement in the chronic age-related low-grade inflammation dubbed inflammaging. Although many aspects of their biology are still controversial, available data suggest that these mitokines have an anti-inflammatory role and increase with age. Therefore, we hypothesize that they can be considered part of an adaptive and integrated immune-metabolic mechanism activated by mitochondrial dysfunction that acts within the framework of a larger anti-inflammatory network aimed at controlling both acute inflammation and inflammaging.

Download Full-text