Nuclear JAK2

Dawson, Mark A.; Bannister, Andrew J.; Saunders, Lindsay; Abdel-Wahab, Omar; Liu, Fan; Nimer, Stephen D.; Levine, Ross L.; Göttgens, Berthold; Kouzarides, Tony; Green, Anthony

doi:10.1182/blood-2011-10-385278

Cited by 8 publications

(4 citation statements)

References 15 publications

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“…In fact, endogenous JAK2 is found almost exclusively in the cytoplasm (including the nucleus) but is not detectable at the plasma membrane (Dawson et al, 2009). This mode of subcellular localization has been later confirmed independently elsewhere including in mammary cells (Dawson et al, 2011). While N-Ras and K-Ras-4B have an identical effector binding loop, we and others have shown that they localize to and signal from different cell compartments —whereas a large portion of N-Ras is cytoplasmic, K-Ras-4B is almost exclusively on the plasma membrane (see Discussion).…”

Section: Resultssupporting

confidence: 64%

Wild-Type N-Ras, Overexpressed in Basal-like Breast Cancer, Promotes Tumor Formation by Inducing IL-8 Secretion via JAK2 Activation

Zheng

Tian

et al. 2015

Cell Reports

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SUMMARY Basal-like breast cancers (BLBCs) are aggressive, and their drivers are unclear. We have found that wild-type N-RAS is overexpressed in BLBCs, but not in other breast cancer subtypes. Repressing N-RAS inhibits transformation and tumor growth, while overexpression enhances these processes even in preinvasive BLBC cells. We identified N-Ras-responsive genes, most of which encode chemokines, e.g., IL8. Expression levels of these chemokines and N-RAS in tumors correlate with outcome. N-Ras, but not K-Ras, induces IL8 by binding and activating the cytoplasmic pool of JAK2; IL8 then acts on both the cancer cells and stromal fibroblasts. Thus BLBC progression is promoted by increasing activities of wild-type N-Ras, which mediates autocrine/paracrine signaling that can influence both cancer and stroma cells.

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Section: Resultssupporting

confidence: 64%

Wild-Type N-Ras, Overexpressed in Basal-like Breast Cancer, Promotes Tumor Formation by Inducing IL-8 Secretion via JAK2 Activation

Zheng

Tian

et al. 2015

Cell Reports

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“…[65][66][67][68][69] Because nuclear PAX5-JAK2 interacts with chromatin, it may well be involved in chromatin modifications, as recently described for nuclear JAK2. [70][71][72] Together, our data support the concept that PAX5 chimeras have distinct properties conferred by the partner proteins, which are likely to shape their function and impact on leukemia development. 14 Our findings regarding the tyrosine phosphorylation in the JH1 kinase domain of PAX5-JAK2 raise the question by which mechanism it may occur.…”

Section: Discussionsupporting

confidence: 62%

The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia

Schinnerl

Fortschegger

Kauer

et al. 2015

Blood

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Key Points• PAX5-JAK2 is the first nuclear DNA-binding JAK2 fusion protein with kinase activity.• JAK2 inhibitors block the kinase activity of PAX5-JAK2.PAX5-JAK2 has recently been identified as a novel recurrent fusion gene in B-cell precursor acute lymphoblastic leukemia, but the function of the encoded chimeric proteinhas not yet been characterized in detail. Herein we show that the PAX5-JAK2 chimera, which consists of the DNA-binding paired domain of PAX5 and the active kinase domain of JAK2, is a nuclear protein that has the ability to bind to wild-type PAX5 target loci. Moreover, our data provide compelling evidence that PAX5-JAK2 functions as a nuclear catalytically active kinase that autophosphorylates and in turn phosphorylates and activates downstream signal transducers and activators of transcription (STATs) in an apparently noncanonical mode. The chimeric protein also enables cytokine-independent growth of Ba/F3 cells and therefore possesses transforming potential. Importantly, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors, rendering it a potential target for therapeutic intervention. Together, our data show that PAX5-JAK2 simultaneously deregulates the PAX5 downstream transcriptional program and activates the Janus kinase-STAT signaling cascade and thus, by interfering with these two important pathways, may promote leukemogenesis. (Blood. 2015;125(8):1282-1291 IntroductionThe fusion protein PAX5-JAK2 has been recurrently detected in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).1-4 Both fusion partner proteins play key roles in hematopoiesis, and somatic mutations in their encoding genes have been found in different hematologic neoplasms. 5-7The paired box transcription factor PAX5, a master regulator of B-cell commitment and maintenance, 6 is a frequent target of genetic alterations in BCP-ALL. 5,8 In ;2% to 3% of the cases, structural rearrangements result in the expression of PAX5 in-frame fusion genes. 1,2,4,5,[8][9][10] PAX5 fusion partners comprise a heterogeneous group of genes encoding transcription factors, structural proteins, kinases, and genes with thus far unknown functions. 1,2,8,9,[11][12][13] Regardless of the functional and structural diversity of the fusion partners, a unique feature of PAX5 fusions is the retention of the PAX5 DNA-binding domain, conferring nuclear localization and the ability to occupy PAX5 target sites. 14 Generally, it is hypothesized that PAX5 fusions act as aberrant transcription factors antagonizing wild-type PAX5 function in a dominant negative mode. 1,8,9,11,[15][16][17][18] However, in a recent study, we have shown that a subset of the PAX5 fusion proteins may have a cellular context-dependent activation potential, indicating that some PAX5 fusions may also activate target genes, thus arguing against their simplified trans-dominant negative function. 14 Janus kinase 2 (JAK2) belongs to a family of nonreceptor tyrosine kinases and is involved in signal transduction from many cytokine and growth hormone receptors ...

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“…JAK2 localizes to the plasma membrane (13, 14), cytoplasm (14-17), and the endoplasmic reticulum (18). Some (14,15,17,(19)(20)(21)(22) but not all (23) reports have described nuclear localization of JAK2. Unexpectedly, JAK2 also associates with microtubules (MT) in cells and directly phosphorylates ␣/␤-tubulin in vitro and in vivo (24).…”

mentioning

confidence: 99%

JAK2 Tyrosine Kinase Phosphorylates and Is Negatively Regulated by Centrosomal Protein Ninein

Jay

Hammer

Nestor-Kalinoski

et al. 2015

Molecular and Cellular Biology

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JAK2 is a cytoplasmic tyrosine kinase critical for cytokine signaling. In this study, we have identified a novel centrosome-associated complex containing ninein and JAK2. We have found that active JAK2 localizes around the mother centrioles, where it partly colocalizes with ninein, a protein involved in microtubule (MT) nucleation and anchoring. We demonstrated that JAK2 is an important regulator of centrosome function. Depletion of JAK2 or use of JAK2-null cells causes defects in MT anchoring and increased numbers of cells with mitotic defects; however, MT nucleation is unaffected. We showed that JAK2 directly phosphorylates the N terminus of ninein while the C terminus of ninein inhibits JAK2 kinase activity in vitro. Overexpressed wild-type (WT) or C-terminal (amino acids 1179 to 1931) ninein inhibits JAK2. This ninein-dependent inhibition of JAK2 significantly decreases prolactin-and interferon gamma (IFN-␥)-induced tyrosyl phosphorylation of STAT1 and STAT5. Downregulation of ninein enhances JAK2 activation. These results indicate that JAK2 is a novel member of centrosome-associated complex and that this localization regulates both centrosomal function and JAK2 kinase activity, thus controlling cytokine-activated molecular pathways. JAK2 is a tyrosine kinase that is activated by two-thirds of the cytokine/hematopoietin receptor superfamily. JAK2 activation initiates a variety of downstream signaling events that lead to diverse physiological responses to cytokines, including regulation of body growth, hematopoiesis, satiety, lactation, and various immune functions. Upon activation, receptor-bound JAK2 phosphorylates specific tyrosine residues of its downstream targets, activating cell survival/proliferation-promoting signaling pathways (1). One target of JAK2 is a family of transcription factors termed signal transducers and activators of transcription (STATs). STATs exist within the cytoplasm in a latent or inactive state; they are recruited by cytokine receptor complexes through interaction between the receptor or JAK phosphotyrosines and the Src homology 2 (SH2) domain of the STAT protein. Several additional kinase cascades may be activated by JAK2, including phosphoinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Three mechanisms of JAK2 activation at the genetic level have been implicated in hematologic malignancies: point mutations, translocations, and amplifications (reviewed in reference 2). Mutations within the pseudokinase domain of JAK2 were detected in a spectrum of myeloproliferative diseases. A V617F gain-of-function point mutation is the cause of ϳ90% of all polycythemia vera cases and ϳ50% of all essential thrombocythemia and primitive myelofibrosis cases (3, 4). Several additional mutations leading to constitutively active JAK2 have been identified recently in patients, including a JAK2 K539L mutant. A T875N substitution in JAK2 was also identified in megakaryoblastic myeloid leukemia cells. In a patient with trisomy 21 and B cell precursor acute lymphoblastic l...

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Nuclear JAK2

Cited by 8 publications

References 15 publications

Wild-Type N-Ras, Overexpressed in Basal-like Breast Cancer, Promotes Tumor Formation by Inducing IL-8 Secretion via JAK2 Activation

Wild-Type N-Ras, Overexpressed in Basal-like Breast Cancer, Promotes Tumor Formation by Inducing IL-8 Secretion via JAK2 Activation

The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia

JAK2 Tyrosine Kinase Phosphorylates and Is Negatively Regulated by Centrosomal Protein Ninein

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