Molecular interdiction of Src-family kinase signaling in hematopoietic cells

Geahlen, Robert L.; Handley, Misty D.; Harrison, Marietta L.

doi:10.1038/sj.onc.1208078

Cited by 23 publications

(22 citation statements)

References 116 publications

(110 reference statements)

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“…To analyze the role of SFKs in the chemokine induction activities of LL-37 on human primary keratinocytes, the cells were pretreated with SFK-specific chemical inhibitors SU6656 or PP2 [21,22,23], and stimulated with LL-37 alone (3 µg/ml) or together with flagellin (0.5 µg/ml) for 24 h. Synergistic induction of chemokine CXCL8/IL-8 by the combined treatment with LL-37 and flagellin was observed (fig. 1a).…”

Section: Resultsmentioning

confidence: 99%

Signaling Pathways Mediating Chemokine Induction in Keratinocytes by Cathelicidin LL-37 and Flagellin

Nijnik¹,

Pistolic²,

Filewod³

et al. 2012

J Innate Immun

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Cathelicidin LL-37 is a multifunctional immunomodulatory and antimicrobial host defense peptide that has an important role in the immune defenses of the skin and other epithelial barriers. We have previously demonstrated that at physiological concentrations LL-37 synergistically augments the production of immune mediators in response to microbial compounds in human primary keratinocytes. Here we define the signaling mechanisms responsible for this activity. We demonstrate that inhibition of Src family kinases (SFKs) strongly inhibited the synergistic chemokine production in response to LL-37 and flagellin in keratinocytes. SFK activation was induced by LL-37 stimulation and was required for the downstream activation of Akt (protein kinase B) and the transcription factors CREB and ATF1. In cells stimulated with LL-37 and flagellin together, Akt activation was primarily induced by LL-37, while both flagellin and LL-37 contributed to the activation of CREB and ATF1 and consequently chemokine induction. The purinergic receptor P2X₇ was identified as the receptor upstream of SFK activation in LL-37-stimulated keratinocytes. Overall, these findings established the P2X₇–SFK–Akt–CREB/ATF1 signaling pathway activated by LL-37 in primary keratinocytes. These signaling mechanisms mediated the synergistic effects of LL-37 on chemokine production in flagellin-stimulated keratinocytes, and thus might have a role in the immune defenses of the skin and possibly other epithelial barriers.

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Section: Resultsmentioning

confidence: 99%

Signaling Pathways Mediating Chemokine Induction in Keratinocytes by Cathelicidin LL-37 and Flagellin

Nijnik¹,

Pistolic²,

Filewod³

et al. 2012

J Innate Immun

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“…PP2 and herbimycin are tyrosine kinase inhibitors that inhibit SRC and receptor tyrosine kinase activity (9,27,29). The pyrazolopyrimidine compound PP2 inhibits tyrosine kinase activity by binding to a cleft between the NH 2 -and COOH-terminal lobes in an area normally occupied by ATP (10). Herbimycin inhibits kinase function through an irreversible binding to sulfhydryl groups of the kinase (29).…”

Section: Genistein and Butein Inhibit Stimulation Of Glucose Transpormentioning

confidence: 99%

Are tyrosine kinases involved in mediating contraction-stimulated muscle glucose transport?

Wright

Geiger

Han

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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Muscle contractions and insulin stimulate glucose transport into muscle by separate pathways. The contraction-mediated increase in glucose transport is mediated by two mechanisms, one involves the activation of 5Ј-AMP-activated protein kinase (AMPK) and the other involves the activation of calcium/ calmodulin-dependent protein kinase II (CAMKII). The steps leading from the activation of AMPK and CAMKII to the translocation of GLUT4 to the cell surface have not been identified. Studies with the use of the tyrosine kinase inhibitor genistein suggest that one or more tyrosine kinases could be involved in contraction-stimulated glucose transport. The purpose of the present study was to determine the involvement of tyrosine kinases in contraction-stimulated glucose transport in rat soleus and epitrochlearis muscles. Contraction-stimulated glucose transport was completely prevented by pretreatment with genistein (100 M) and the related compound butein (100 M). However, the structurally distinct tyrosine kinase inhibitors 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyridine and herbimycin did not reduce contraction-stimulated glucose transport. Furthermore, genistein and butein inhibited glucose transport even when muscles were exposed to these compounds after being stimulated to contract. Muscle contractions did not result in increases in tyrosine phosphorylation of proteins such as proline-rich tyrosine kinase and SRC. These results provide evidence that tyrosine kinases do not mediate contraction-stimulated glucose transport and that the inhibitory effects of genistein on glucose transport result from direct inhibition of the glucose transporters at the cell surface.5-aminoimidazole-4-carboxamide ribonucleoside; exercise; glucose transporter 4; hypoxia EXERCISE AND INSULIN STIMULATE GLUCOSE TRANSPORT by separate pathways (17). Both 5Ј-AMP-activated protein kinase (AMPK; see Refs. 4,14,19,22,24) and activation of calcium/calmodulin-dependent protein kinase (CAMK)II (32) by increases in cytosolic Ca 2ϩ (33) are involved in mediating the stimulation of muscle glucose uptake by contractions.The signaling mechanisms linking the activation of AMPK and/or CAMK to increases in skeletal muscle glucose transport are not known. However, a number of lines of evidence raised the possibility that activation of one or more tyrosine kinases might be involved in the pathways leading from muscle contractions to an increase in muscle glucose transport. In support of this possibility, it has been reported that activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) results in activation of the proline-rich tyrosine kinase PYK2 in rat skeletal muscle and that the tyrosine kinase inhibitor genistein prevents stimulation of glucose transport by AICAR (7). These investigators concluded that the effects of exercise that are dependent on AMPK are mediated by PYK2. Additionally, stimulation of glucose transport and GLUT4 translocation by osmotic shock in adipocytes and L6 myotubes is prevented by genistein (6, ...

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“…SRC-family kinases play a pivotal role in signaling through surface receptors on hematopoietic cells, and of the nine members of the SRC family, HCK, FGR, and LYN are primarily expressed on myeloid cells (56) and can also be activated by BCR-ABL1 kinase (57). Imatinib resistance and progression to, in particular, lymphoid blast phase has been suggested to be mediated through LYN and HCK upregulation (58,59).…”

Section: Src Overexpressionmentioning

confidence: 99%

Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia

Milojković

Apperley

2009

Clinical Cancer Research

234

181

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Targeted therapy in the form of selective tyrosine kinase inhibitors (TKI) has transformed the approach to management of chronic myeloid leukemia (CML) and dramatically improved patient outcome to the extent that imatinib is currently accepted as the first-line agent for nearly all patients presenting with CML, regardless of the phase of the disease. Impressive clinical responses are obtained in the majority of patients in chronic phase; however, not all patients experience an optimal response to imatinib, and furthermore, the clinical response in a number of patients will not be sustained. The process by which the leukemic cells prove resistant to TKIs and the restoration of BCR-ABL1 signal transduction from previous inhibition has initiated the pursuit for the causal mechanisms of resistance and strategies by which to surmount resistance to therapeutic intervention. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance, however, it is increasingly evident that the presence of mutations does not explain all cases of resistance and does not account for the failure of TKIs to eliminate minimal residual disease in patients who respond optimally. The focus of exploring TKI resistance has expanded to include the mechanism by which the drug is delivered to its target and the impact of drug influx and efflux proteins on TKI bioavailability. The limitations of imatinib have inspired the development of second generation TKIs in order to overcome the effect of resistance to this primary therapy. ( Chronic myeloid leukemia (CML) results from the balanced translocation of c-ABL from chromosome 9 and BCR on chromosome 22 leading to the formation of BCR-ABL1 chimeric oncoprotein, the product of the BCR-ABL1 hybrid gene, with constitutive tyrosine kinase activity (1, 2). Deregulated BCR-ABL1 activity results in enhanced cellular proliferation, and resistance to apoptosis and oncogenesis (3, 4). CML naturally progresses through distinct phases from early chronic phase to an intermediate accelerated phase followed by a terminal blast phase. Imatinib, the first tyrosine kinase inhibitor (TKI) approved for the treatment of CML (5), is a phenylaminopyridimine, which principally targets the tyrosine kinase activity of BCR-ABL1, exclusively binding to BCR-ABL1 in the inactive conformation in addition to inhibitory effects on KIT, ARG, and PDGFR kinases (6). The recent update of the phase III randomized IRIS study (International Randomized Study of Interferon-α plus Ara-C versus STI571) prospectively comparing imatinib with interferon-α and cytarabine in previously untreated patients in first chronic phase showed the best observed rate for a complete cytogenetic response [CCyR; or an undetectable number of Philadelphia chromosome positive (Ph+) chromosomes by conventional metaphase analysis] on imatinib of 82% at 6 years (7), with a declining annual rate of progression as the molecular response improved with time.

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Molecular interdiction of Src-family kinase signaling in hematopoietic cells

Cited by 23 publications

References 116 publications

Signaling Pathways Mediating Chemokine Induction in Keratinocytes by Cathelicidin LL-37 and Flagellin

Signaling Pathways Mediating Chemokine Induction in Keratinocytes by Cathelicidin LL-37 and Flagellin

Are tyrosine kinases involved in mediating contraction-stimulated muscle glucose transport?

Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia

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