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)

Retroviral transduction of primary hematopoietic cells with human oncogenes provides a powerful approach to investigating the molecular mechanisms controlling the normal proliferation and differentiation of these cells. Here we show that primitive human CD34(+) cord blood cells, including multipotent as well as granulopoietic- and erythroid-restricted progenitors, can be efficiently transduced with a MSCV-BCR-ABL-IRES-GFP retrovirus, resulting in the sustained expression by their progeny of very high levels of tyrosine phosphorylated p210(BCR-ABL). Interestingly, even in the presence of growth factors that supported the exclusive production of granulopoietic cells from green fluorescent protein (GFP)-transduced control cells, BCR-ABL-transduced progenitor subpopulations generated large numbers of erythropoietin-independent terminally differentiating erythroid cells and reduced numbers of granulopoietic cells. Analyses of individual clones generated by single transduced cells in both semisolid and liquid cultures showed this BCR-ABL-induced erythroid differentiation response to be elicited at a high frequency from all types of transduced CD34(+) cells independent of their apparent prior lineage commitment status. Additional experiments showed that this erythroid differentiation response was largely prevented when the cells were transduced and maintained in the presence of the BCR-ABL-specific tyrosine kinase inhibitor, STI-571. These findings indicate that overexpression of BCR-ABL in primary human hematopoietic cells can activate an erythroid differentiation program in apparently granulopoietic-restricted cells through a BCR-ABL kinase-dependent mechanism, thus providing a new molecular tool for elucidating mechanisms underlying lineage fate determination in human hematopoietic cells and infidelity in human leukemia.
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PMID:Modulation of p210(BCR-ABL) activity in transduced primary human hematopoietic cells controls lineage programming. 1196 83

Signaling through hematopoietic cytokine receptors such as the erythropoietin receptor (EpoR) depends on the activation of a receptor-bound Janus kinase (JAK) and tyrosine phosphorylation of the cytoplasmic domain. To visualize the EpoR and elucidate structural requirements coordinating signal transduction, we probed the EpoR by inserting the green fluorescent protein (GFP) at various positions. We show that insertion of GFP in proximity to the transmembrane domain, either in the extracellular or the cytoplasmic domain, results in EpoR-GFP receptors incompetent to elicit biological responses in a factor-dependent cell line or in erythroid progenitor cells. Surprisingly, a receptor harboring GFP insertion in the middle of the cytoplasmic domain, and thereby separating the JAK2 binding site from the tyrosine residues, is capable of supporting signal transduction in response to ligand binding. Comparable with the wild type EpoR, but more efficient than a C-terminal EpoR-GFP fusion, this chimeric receptor promotes the maturation of erythroid progenitor cells and is localized in punctated endosome-like structures. We conclude that the extracellular, transmembrane, and membrane-proximal segment of the cytoplasmic domain form a rigid structural entity whose precise orientation is essential for the initiation of signal transduction, whereas the cytoplasmic domain possesses flexibility in adopting an activated conformation.
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PMID:A functional green fluorescent protein-erythropoietin receptor despite physical separation of JAK2 binding site and tyrosine residues. 1199 94

Erythropoietin (Epo) is a hematopoietic cytokine that is crucial for the differentiation and proliferation of erythroid progenitor cells. Epo acts on its target cells by inducing homodimerization of the erythropoietin receptor (EpoR), thereby triggering intracellular signaling cascades. The EpoR encompasses eight tyrosine motifs on its cytoplasmic tail that have been shown to recruit a number of regulatory proteins. Recently, the feedback inhibitor suppressor of cytokine signaling-3 (SOCS-3), also referred to as cytokine-inducible SH2-containing protein 3 (CIS-3), has been shown to act on Epo signaling by both binding to the EpoR and the EpoR-associated Janus kinase 2 (Jak2) [Sasaki, A., Yasukawa, H., Shouda, T., Kitamura, T., Dikic, I. & Yoshimura, A. (2000) J. Biol. Chem 275, 29338-29347]. In this study tyrosine 401 was identified as a binding site for SOCS-3 on the EpoR. Here we show that human SOCS-3 binds to pY401 with a Kd of 9.5 microm while another EpoR tyrosine motif, pY429pY431, can also interact with SOCS-3 but with a ninefold higher affinity than we found for the previously reported motif pY401. In addition, SOCS-3 binds the double phosphorylated motif pY429pY431 more potently than the respective singly phosphorylated tyrosines indicating a synergistic effect of these two tyrosine residues with respect to SOCS-3 binding. Surface plasmon resonance analysis, together with peptide precipitation assays and model structures of the SH2 domain of SOCS-3 complexed with EpoR peptides, provide evidence for pY429pY431 being a new high affinity binding site for SOCS-3 on the EpoR.
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PMID:A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor. 1202 90

The chimaeric BCR-ABL oncoprotein is the molecular hallmark of chronic myeloid leukaemia (CML). Expression of Bcr-Abl has been associated with arrested differentiation as well as resistance to apoptosis. The downstream pathway involved in apoptosis resistance has been extensively studied, whereas the role of Bcr-Abl in cell differentiation is largely unclear. A recent report has shown that Bcr-Abl expression alone is sufficient to increase the number of multipotent and myeloid lineage-committed progenitors in a dose-dependent manner while suppressing the development of committed erythroid progenitors. In accordance with this model, downregulation of c-Abl and Bcr-Abl has been observed during differentiation in different systems, although the mechanism is still largely unknown. To investigate the relationship between erythroid differentiation and c-Abl and Bcr-Abl levels, we induced differentiation in K562 cells using a temperature-inducible p53 mutant (p53Val1335). It was found that p53-induced erythroid differentiation in K562 cells required caspase activity. During this process, caspase-dependent cleavage of c-Abl and Bcr-Abl tyrosine kinases was observed, suggesting a new mechanism for the downregulation of the kinases during erythroid differentiation.
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PMID:p53 expression in K562 cells is associated with caspase-mediated cleavage of c-ABL and BCR-ABL protein kinases. 1202 26

Several patients with clinical features of chronic myeloid leukemia (CML) have fusion of the TEL (ETV6) gene on 12p13 with ABL on 9q34 and express a chimeric Tel-Abl protein that contains the same portion of the Abl tyrosine kinase fused to Tel, an Ets family transcription factor, rather than Bcr. In a murine retroviral bone marrow transduction-transplantation model, a Tel (exon 1-5)-Abl fusion protein induced 2 distinct illnesses: a CML-like myeloproliferative disease very similar to that induced by Bcr-Abl but with increased latency and a novel syndrome characterized by small-bowel myeloid cell infiltration and necrosis, increased circulating endotoxin and tumor necrosis factor alpha levels, and fulminant hepatic and renal failure. Induction of both diseases required the Tel pointed homology oligomerization domain and Abl tyrosine kinase activity. Myeloid cells from mice with both diseases expressed Tel-Abl protein. CML-like disease induced by Tel-Abl and Bcr-Abl was polyclonal and originated from cells with multilineage (myeloid, erythroid, and B- and T-lymphoid) repopulating ability and the capacity to generate day-12 spleen colonies in secondary transplantations. In contrast to findings with Bcr-Abl, however, neither Tel-Abl-induced disease could be adoptively transferred to irradiated secondary recipient syngeneic mice. These results show that Tel-Abl has leukemogenic properties from distinct from those of Bcr-Abl and may act in a different bone marrow progenitor.
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PMID:The Tel-Abl (ETV6-Abl) tyrosine kinase, product of complex (9;12) translocations in human leukemia, induces distinct myeloproliferative disease in mice. 1203 90

Erythropoietin, in its standard role for the treatment of anemia, is often mechanistically regarded simply as increasing blood oxygen-carrying capacity and hence decreasing tumor hypoxia. In reality, erythropoietin (a member of the cytokine superfamily) is expressed in a multitude of tissues/cell types including erythroid and cancer cells, and the liver and central nervous system. Erythropoietin expression is induced by hypoxia-inducible factor-1, which itself is induced during hypoxia. Whereas it has no endogenous tyrosine kinase activity of its own, erythropoietin, via constitutively associated JAK2, can activate several signaling pathways including STAT5, RAS, and phosphoinositol 3-kinase. An increased understanding of these pathways is already opening up new clinical indications, particularly in terms of oncology and neurology. Current arrays/molecular endpoint studies in clinical trials should identify key components of the particular signaling pathways that will guide further use in the development of both better synergistic therapies as well as new molecular targets.
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PMID:Evidence for erythropoietin as a molecular targeting agent. 1213 9

We recorded elevated numbers of circulating myeloid and erythroid colony-forming cells in 15 adult patients with acute myeloid leukaemia (AML) who presented with high blood white cell counts. Since leukaemic blasts from three of these patients were Philadelphia chromosome-positive (Ph+), we were able to determine if blood progenitors from these particular patients arose from the leukaemic clone or from residual normal progenitors. Blasts and colonies were intensively investigated using a combination of cell surface marker analysis by flow cytometry, RT-PCR and interphase fluorescence in situ hybridization (FISH). FISH detected rearrangements within the major breakpoint BCR (M-BCR) region in blasts and in some myeloid and erythroid colonies from patients 1 and 2. The minor breakpoint (m-BCR) region was detected in blasts and in some myeloid and erythroid colonies from patient 3. RT-PCR detected long b2a2 BCR-ABL transcripts in blasts from patients 1 and 2, although misspliced short e1a2 transcripts were also seen in patient 1. Only e1a2 transcripts were found in blasts from patient 3. Flow sorting demonstrated the B-cell marker CD19 on blasts and on a proportion of myeloid and erythroid progenitors from patients 1 and 3. RT-PCR also detected IgH rearrangements, further evidence of B-cell differentiation, in blasts from these two patients. We conclude that both normal and clonal circulating progenitor numbers can be raised in both M-BCR and m-BCR Ph+ AML. The underlying cause, perhaps efflux from a congested marrow, may be common to AML patients with a high blood white cell count.
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PMID:Increased circulating normal and BCR-ABL+Ve progenitor numbers in Philadelphia chromosome-positive acute myeloid leukaemia. 1236 61

CD45 is a membrane-associated tyrosine phosphatase that dephosphorylates Src family kinases and Janus kinases (JAKs). To clarify the role of CD45 in hematopoietic differentiation, we examined the effects of anti-CD45 monoclonal antibody NU-L(PAN) on the proliferation and differentiation of umbilical cord blood CD34(+) cells. NU-L(PAN) showed a prominent inhibition of the proliferation of CD34(+) cells induced by the mouse bone marrow stromal cell line MS-5 or erythropoietin (EPO). However, NU-L(PAN) did not affect the proliferation induced by interleukin 3. NU-L(PAN) also inhibited MS-5-induced or EPO-induced erythroid differentiation of CD34(+) cells. The cells stimulated with EPO in the presence of NU-L(PAN) morphologically showed differentiation arrest at the stage of basophilic erythroblasts after 11 days of culture, whereas the cells treated with EPO without NU-L(PAN) differentiated into mature red blood cells. The Src family kinase Lyn and JAK2 were phosphorylated when erythroblasts obtained after 4 days of culture of CD34(+) cells in the presence of EPO were restimulated with EPO. Overnight NU-L(PAN) treatment before addition of EPO reduced the phosphorylation of Lyn but not that of JAK2. Simultaneously, the enhancement of Lyn kinase activity after restimulation with EPO was reduced by NU-L(PAN) treatment. These results indicate selective inactivation of Lyn by CD45 activated with NU-L(PAN) and could partly explain the inhibitory mechanism on erythropoiesis exhibited by EPO. These findings suggest that CD45 may play a pivotal role in erythropoiesis.
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PMID:CD45 tyrosine phosphatase inhibits erythroid differentiation of umbilical cord blood CD34+ cells associated with selective inactivation of Lyn. 1239 28

The classification of chronic neutrophilic leukemia (CNL) is controversial. Our purpose was to correlate clinical, pathologic, and molecular analyses in 2 cases of CNL. In both cases, the patients were referred because of a substantially increased peripheral WBC count noted during routine examination. Bone marrow biopsies and aspirate smears revealed hypercellularity with myeloid/erythroid ratios of 4:1 and 11:1, respectively. The bone marrow aspirate results were as follows: case 1: blasts, 2%; promyelocytes, 2%; myelocytes, 6%; metamyelocytes, 16%; band neutrophils, 13%; segmented neutrophils, 34%; and case 2: blasts, 1%; promyelocytes, 2%; myelocytes, 15%; metamyelocytes, 20%; band neutrophils, 24%; neutrophils, 19%. Reverse transcriptase in situ polymerase chain reaction studies demonstrated expression of mu-BCR-ABL transcripts in 13% and 25% of the bone marrow cells, respectively. In both cases, the positive signal was noted mainly in the early granulocytic precursors and was present in occasional mature neutrophils. To our knowledge, this is thefirst in situ demonstration of mu-BCR-ABL expression in CNL Ourfindings reinforce the usefulness of this messenger RNA as a molecular marker of CNL.
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PMID:Expression of mu-BCR-ADL transcripts in chronic neutrophilic leukemia. 1247 76

Several reports have suggested an interaction between the erythropoietin receptor (EpoR) and the shared signaling subunit (hbeta(c)) of the human granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 receptors, although the functional consequences of this interaction are unclear. We previously showed that in vivo expression of constitutively active extracellular (EC) mutants of hbeta(c) induces erythrocytosis and Epo independence of erythroid colony-forming units (CFU-E). This occurs despite an apparent requirement of these mutants for the GM-CSF receptor alpha-subunit (GMRalpha), which is not expressed in CFU-E. Here, we show that coexpression of hbeta(c) EC mutants and EpoR in BaF-B03 cells, which lack GMRalpha, results in factor-independent proliferation and JAK2 activation. Mutant receptors that cannot activate JAK2 fail to produce a functional interaction. As there is no detectable phosphorylation of hbeta(c) on intracellular tyrosine residues, EpoR displays constitutive tyrosine phosphorylation. These observations suggest that JAK2 activation mediates cross-talk between EC mutants of hbeta(c) and EpoR. The implications of these data are discussed as are our findings that activated hbeta(c) mutants can functionally interact with certain other cytokine receptors.
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PMID:Functional cross-talk between cytokine receptors revealed by activating mutations in the extracellular domain of the beta-subunit of the GM-CSF receptor. 1248 7


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