Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding the molecular basis for the many actions of growth hormone (GH) has been challenging because many of these actions are only evident in vivo. Recently, STAT5b has emerged as a key GH signaling intermediate in the regulation of postnatal growth, adiposity and sexual dimorphism of hepatic gene expression. This realization is based on targeted disruption or mutation of the GH receptor and its signaling components, together with clinical studies of GH-insensitive mutants. Microarray analysis of liver from GH receptor and signal transducer and activation of transcription 5b (STAT5b)-deleted mice have identified a range of relevant transcripts regulated by the Janus kinase 2/STAT5b signaling pathway. In addition, many transcripts are regulated independently of STAT5b, presumably as a result of PtdIns 3-kinase, extracellular-regulated kinase and Src signaling by this pleiotropic cytokine receptor.
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PMID:How growth hormone controls growth, obesity and sexual dimorphism. 1806 38

The majority of the BCR-ABL-negative myeloproliferative disorders express the mutant JAK2, JAK2V617F. Previously we showed that constitutive activation of this oncogenic JAK2 mutant in Ba/F3 or 32D cells requires coexpression of a cognate homodimeric cytokine receptor, such as the EpoR. However, overexpression of JAK2V617F in Ba/F3 cells renders them cytokine-independent for growth in the absence of an exogenous cytokine receptor. Here, we demonstrated that JAK2V617F domains required for receptor association are essential for cytokine-independent growth by overexpressed JAK2V617F, suggesting JAK2V617F is binding to an unknown endogenous cytokine receptor(s) for its activation. We further showed that disruption of EpoR dimerization by coexpressing a truncated EpoR disrupted JAK2V617F-mediated transformation, indicating that EpoR dimerization plays an essential role in the activation of JAK2V617F. Interestingly, coexpression of JAK2V617F with EpoR mutants that retain JAK2 binding but are defective in mediating Epo-dependent JAK2 activation due to mutations in a conserved juxtamembrane motif does lead to cytokine-independent activation of JAK2V617F. Overall, these findings confirm that JAK2V617F requires binding to a dimerized cytokine receptor for its activation, and that the key EpoR juxtamembrane regulatory motif essential for Epo-dependent JAK2 activation is not essential for the activation of JAK2V617F. The structure of the activated JAK2V617F is thus likely to be different from that of the activated wild-type JAK2, raising the possibility of developing a specifically targeted therapy for myeloproliferative disorders.
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PMID:Dimerization by a cytokine receptor is necessary for constitutive activation of JAK2V617F. 1815 85

Many cytokines initiate cellular responses through their interaction with members of the cytokine receptor superfamily. This family of receptors contains no catalytic domains in the cytoplasmic domain, but all couple ligand binding to tyrosine phosphorylation, and this activity requires a membrane-proximal region that contains some similarity among the receptors. Recent studies have shown that members of the JAK family of protein tyrosine kinases associate with the membraneproximal region, are rapidly tyrosine-phosphorylated following ligand binding, and their in vitro kinase activity is activated. The JAK family of kinases is characterized by two kinase domains, only one of which contains all of the hallmarks of active kinases. This family of 130-kD kinases lacks SH2 or SH3 domains, but family members contain extensive homology in the large amino terminal region. Individual receptors associate with, or require, one or more of the three known family members including JAKI, JAK2, and tyk2. Putative substrates of the JAK family of kinases include the 91-kD and 113-kD proteins of the interferon-stimulated transcription complex ISGF3 that, when tyrosinephosphorylated, migrate to the nucleus and participate in the activation of gene transcription. Recent evidence suggests that the 91- and 113-kD proteins are members of a large family of genes that are potential substrates o f JAK family members and may regulate a variety o f genes involved in cell growth, differentiation, or function. Together the data provide a new, generalized model for the mechanisms by which cytokines that utilize receptors of the cytokine receptor superfamily regulate cellular activity.
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PMID:Signaling by the cytokine receptor superfamily just another kinase story. 1840

Recent data have shed significant new light on the mechanisms involved in the transmission of a biologic signal by GH. Following ligand-induced dimerization of the GH receptor, multiple cascades are involved in GH signaling. These include activation of nonreceptor tyrosine kinases, in particular JAK2, which is a mechanism shared by the newly described cytokine receptor superfamily. Furthermore, several classic pathways (for example, guanine-nucleotide-binding proteins and protein kinase C), shared by numerous hormones, growth factors, and neurotransmitters, are also involved in many of the actions of GH. The interrelationships between the various signaling pathways for GH have not yet been fully defined. This review briefly summarizes the current state of knowledge with respect to the processes involved in the effects of GH in target cells.
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PMID:Postreceptor signaling mechanisms for Growth Hormone. 1840 2

The four mammalian Janus kinase (JAK) family members, JAK1, JAK2, JAK3 and TYK2, are non-receptor protein tyrosine kinases (PTKs) that are crucial for cytokine receptor signaling in blood formation and immune responses. Mutations and translocations in the JAK genes leading to constitutively active JAK proteins are associated with a variety of hematopoietic malignancies, including the myeloproliferative disorders (JAK2), acute lymphoblastic leukemia (JAK2), acute myeloid leukemia (JAK2, JAK1), acute megakaryoblastic leukemia (JAK2, JAK3) and T-cell precursor acute lymphoblastic leukemia (JAK1). In contrast, loss-of-function mutations of JAK3 and TYK2 lead to immunodeficiency. The role of JAKs as therapeutic targets is starting to expand, as more insights into their structure and activation mechanisms become available.
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PMID:JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. 1868 96

The BCR-ABL-negative myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), entered the spotlight in 2005 when the unique somatic acquired JAK2 V617F mutation was described in >95% of PV and in 50% of ET and PMF patients. For the very rare PV patients who do not harbor the JAK2 V617F mutation, exon 12 JAK2 mutants were discovered also to result in activated forms of JAK2. A minority of ET and PMF patients harbor mutations that constitutively activate the thrombopoietin receptor (TpoR). In bone marrow reconstitution models based on retroviral transduction, the phenotype induced by JAK2 V617F is less severe and different from the rapid fatal myelofibrosis induced by TpoR W515L. The reasons for these differences are unknown. Exactly by which mechanism(s) one acquired somatic mutation, JAK2 V617F, can promote three different diseases remains a mystery, although gene dosage and host genetic variation might have important functions. We review the recent progress made in deciphering signaling anomalies in PV, ET and PMF, with an emphasis on the relationship between JAK2 V617F and cytokine receptor signaling and on cross-talk with several other signaling pathways.
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PMID:Aberrant signal transduction pathways in myeloproliferative neoplasms. 1876 48

A gain-of-function mutation (V617F) in the pseudokinase domain of JAK2 is frequently present in patients with myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis. This mutation might serve as an important diagnostic biomarker for these uncommon diseases and may represent a target for novel therapy. It is imperative that a well-defined molecular mechanism be provided to account for the gain of function. This manuscript focuses on whether the V617F mutation is sufficient to cause constitutive activation of the enzyme. The evidence presented suggests that the V617F mutation would not cause constitutive activation because its hyperactivating effect is not observed when the mutation is combined with the YY1007,1008FF mutations. The phosphorylation of these two tyrosines within the activation loop is generally accepted as an essential step in the enzyme's normal transition from a basal state of activity to a fully active catalytic state following cytokine receptor stimulation. These observations are consistent with an interpretation that V617F-induced hyperactivation does not supersede the requirement for receptor-mediated activation, as others have shown by combining the V617F mutation with critical mutations in the enzyme's FERM domain. Thus, JAK2(V617F) should be considered as a hyperactive kinase rather than a constitutively active kinase.
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PMID:Activation loop tyrosines allow the JAK2(V617F) mutant to attain hyperactivation. 1884 97

Activating mutations in JAK1 have been reported in acute lymphoblastic leukemias, but little is known about the mechanisms involved in their constitutive activation. Here, we studied the ability of JAK1 V658F and A634D to activate the Janus kinase (JAK)/STAT pathway upon ectopic expression in HEK293 cells alone or together with the other components of the interleukin-9 receptor complex (IL-9Ralpha, gammac, and JAK3). Expression of JAK1 mutants alone failed to trigger STAT activation, but co-expression of the IL-9Ralpha chain promoted JAK1 mutant phosphorylation and STAT activation. Mutation of the FERM domain of JAK1, which is critical for cytokine receptor association, or of the single tyrosine of IL-9Ralpha involved in STAT recruitment abolished this activity, indicating that JAK1 mutants need to associate with a functional IL-9Ralpha to activate STAT factors. Several lines of evidence indicated that IL-9Ralpha homodimerization was involved in this process. IL-9Ralpha variants with mutations of the JAK-interacting BOX1 region not only failed to promote JAK1 activation but also acted as dominant negative forms reverting the effect of wild-type IL-9Ralpha. Coimmunoprecipitation experiments also showed the formation of IL-9Ralpha homodimers. Interestingly, STAT activation was partially inhibited by expression of gammac, suggesting that overlapping residues are involved in IL-9Ralpha homodimerization and IL-9Ralpha/gammac heterodimerization. Co-expression of wild-type JAK3 partially reverted the inhibition by gammac, indicating that JAK3 cooperates with JAK1 mutants within the IL-9 receptor complex. Similar results were observed with IL-2Rbeta. Taken together, our results show that IL-9Ralpha and IL-2Rbeta homodimers efficiently mediate constitutive activation of ALL-associated JAK1 mutants.
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PMID:Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers. 1913 2

Mutations of the IL2RG encoding the common gamma-chain (gamma(c)) lead to the X-linked SCID disease. Gene correction through ex vivo retroviral transduction restored the immunological impairment in the most of treated patients, although lymphoproliferative events occurred in five of them. Even though in two cases it was clearly documented an insertional mutagenesis in LMO2, it is conceivable that gamma(c) could have a role per se in malignant lymphoproliferation. The gamma(c) is a shared cytokine receptor subunit, involved also in growth hormone (GH) receptor signaling. Through short interfering RNA or using X-linked SCID B lymphoblastoid cell lines lacking gamma(c), we demonstrate that self-sufficient growth was strongly dependent on gamma(c) expression. Furthermore, a correlation between gamma(c) amount and the extent of constitutive activation of JAK3 was found. The reduction of gamma(c) protein expression also reduced GH-induced proliferation and STAT5 nuclear translocation in B lymphoblastoid cell lines. Hence, our data demonstrate that gamma(c) plays a remarkable role in either spontaneous or GH-induced cell cycle progression depending on the amount of protein expression, suggesting a potential role as enhancing cofactor in lymphoproliferation.
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PMID:The cellular amount of the common gamma-chain influences spontaneous or induced cell proliferation. 1923 29

The activating W515L mutation in the thrombopoietin receptor (MPL) has been identified in primary myelofibrosis and essential thrombocythemia. MPL belongs to a subset of the cytokine receptor superfamily that requires the JAK2 kinase for signaling. We examined whether the ligand-independent MPL(W515L) mutant could signal intracellularly. Addition of the endoplasmic reticulum (ER) retention KDEL sequence to the receptor C terminus efficiently locked MPL(W515L) within its natural ER/Golgi maturation pathway. In contrast to cells expressing the parental MPL(W515L), MPL(W515L)-KDEL-expressing FDC-P1 cells were unable to grow autonomously and to produce tumors in nude mice. When observed, tumor nodules resulted from in vivo selection of cells leaking the receptor at their surface. JAK2 co-immunoprecipitated with MPL(W515L)-KDEL but was not phosphorylated. We generated disulfide-bonded MPL(W515L) homodimers by the S402C substitution, both in the normal and KDEL context. Unlike MPL(W515L)-KDEL, MPL(W515L-S402C)-KDEL signaled constitutively and exhibited cell surface localization. These data establish that MPL(W515L) with appended JAK2 matures through the ER/Golgi system in an inactive conformation and suggest that the MPL(W515L)/JAK2 complex requires membrane localization for JAK2 phosphorylation, resulting in autonomous receptor signaling.
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PMID:Ligand-independent thrombopoietin mutant receptor requires cell surface localization for endogenous activity. 1926 14


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