Rapid redistribution of F-actin induced by NGF and cyclicamp in PC12D cells was inhibited by specific protein kinase inhibitors

Protein kinases play critical roles in the control of cell growth, proliferation, migration, and angiogenesis, through their catalytic activity. Over the past years, numerous protein kinase inhibitors have been identified and are being successfully used clinically. Traditional Chinese medicine (TCM) represents a large class of bioactive substances, and some of them display anticancer activity via inhibiting protein kinases signal pathway. Some of the TCM have been used to treat tumors clinically in China for many years. The p38mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase, serine/threonine-specific protein kinases (PI3K/AKT/mTOR), and extracellular signal-regulated kinases (ERK) pathways are considered important signals in cancer cell development. In the present article, the recent progress of TCM that exhibited significant inhibitory activity towards a range of protein kinases is discussed. The clinical efficacy of TCM with inhibitory effects on protein kinases in treating a tumor is also presented. The article also discussed the prospects and problems in the development of anticancer agents with TCM.

Download Full-text

6-Dimethyl amino purine and 2-amino purine inhibit the induction of expresion of milk protein genes by prolactin

Bioscience Reports ◽

10.1007/bf01121788 ◽

1992 ◽

Vol 12 (3) ◽

pp. 189-197 ◽

Cited By ~ 2

Author(s):

Mahasti Bayat-Sarmadi ◽

Rachel Maliénou-Ngassa ◽

Claudine Puissant ◽

Louis-Marie Houdebine

Keyword(s):

Protein Kinase ◽

Milk Protein ◽

Kinase Inhibitors ◽

Specific Protein ◽

Protein Kinase Inhibitors ◽

Experimental Conditions ◽

Kinase C ◽

Milk Protein Genes ◽

Actin Mrna ◽

First Time

Two protein kinase-inhibitors, 6-dimethyl amino purine and 2-amino purine inhibited induction of β-casein synthesis by prolactin when added to the culture medium of rabbit mammary explant and cells. The accumulation of the mRNA for αs1- and β-caseins and for whey acidic protein did not take place in the presence of the inhibitors whereas β-actin mRNA concentration was not altered. In the same experimental conditions, H7, an inhibitor of protein kinase C and, to a lower extent, of protein kinase A did not prevent prolactin from acting. These data suggest for the first time that specific protein kinases are involved in the transduction of the prolactin signal to milk protein genes.

Download Full-text

The specificities of protein kinase inhibitors: an update

Biochemical Journal ◽

10.1042/bj20021535 ◽

2003 ◽

Vol 371 (1) ◽

pp. 199-204 ◽

Cited By ~ 980

Author(s):

Jenny BAIN ◽

Hilary McLAUCHLAN ◽

Matthew ELLIOTT ◽

Philip COHEN

Keyword(s):

Protein Kinase ◽

Protein Kinases ◽

Kinase Inhibitors ◽

Glycogen Synthase ◽

Specific Protein ◽

Protein Kinase Inhibitors ◽

Glycogen Synthase Kinase 3 ◽

Dual Specificity ◽

Combined Use ◽

Dependent Protein

We have previously examined the specificities of 28 commercially available compounds, reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases [Davies, Reddy, Caivano and Cohen (2000) Biochem. J. 351, 95—105]. In the present study, we have extended this analysis to a further 14 compounds. Of these, indirubin-3′-monoxime, SP 600125, KT 5823 and ML-9 were found to inhibit a number of protein kinases and conclusions drawn from their use in cell-based assays are likely to be erroneous. Kenpaullone, Alsterpaullone, Purvalanol, Roscovitine, pyrazolopyrimidine 1 (PP1), PP2 and ML-7 were more specific, but still inhibited two or more protein kinases with similar potency. Our results suggest that the combined use of Roscovitine and Kenpaullone may be useful for identifying substrates and physiological roles of cyclin-dependent protein kinases, whereas the combined use of Kenpaullone and LiCl may be useful for identifying substrates and physiological roles of glycogen synthase kinase 3. The combined use of SU 6656 and either PP1 or PP2 may be useful for identifying substrates of Src family members. Epigallocatechin 3-gallate, one of the main polyphenolic constituents of tea, inhibited two of the 28 protein kinases in the panel, dual-specificity, tyrosine-phosphorylated and regulated kinase 1A (DYRK1A; IC50 = 0.33μM) and p38-regulated/activated kinase (PRAK; IC50 = 1.0μM).

Download Full-text

Specificity and mechanism of action of some commonly used protein kinase inhibitors

Biochemical Journal ◽

10.1042/bj3510095 ◽

2000 ◽

Vol 351 (1) ◽

pp. 95-105 ◽

Cited By ~ 1822

Author(s):

Stephen P. DAVIES ◽

Helen REDDY ◽

Matilde CAIVANO ◽

Philip COHEN

Keyword(s):

Protein Kinase ◽

Protein Kinases ◽

Kinase Inhibitors ◽

Specific Protein ◽

Protein Kinase Inhibitors ◽

Mitogen Activated Protein Kinase ◽

Phosphatidylinositol 3 Kinase ◽

Selective Inhibitors ◽

Mitogen Activated Protein ◽

Additional Protein

The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.

Download Full-text

Engagement of interleukin-7 receptor stimulates tyrosine phosphorylation, phosphoinositide turnover, and clonal proliferation of human T-lineage acute lymphoblastic leukemia cells

Blood ◽

10.1182/blood.v78.3.564.564 ◽

1991 ◽

Vol 78 (3) ◽

pp. 564-570 ◽

Cited By ~ 48

Author(s):

I Dibirdik ◽

MC Langlie ◽

JA Ledbetter ◽

L Tuel-Ahlgren ◽

V Obuz ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Protein Kinase ◽

Tyrosine Phosphorylation ◽

Kinase Inhibitor ◽

Lymphoblastic Leukemia ◽

Specific Protein ◽

Protein Kinase Inhibitors ◽

In Vitro Proliferation ◽

Interleukin 7 ◽

Specific Protein Kinase

Abstract The purposes of this study were to examine the biologic effects of the engagement of the interleukin-7 receptor (IL-7R) with recombinant human interleukin-7 (rhIL-7) in immunophenotypically distinct T-lineage acute lymphoblastic leukemia (ALL) blasts and to elucidate the biochemical nature of the IL-7R-linked transmembrane signal in rhIL-7-responsive T- lineage ALL blast populations. In the absence of costimulants, rhIL-7 stimulated the in vitro proliferation and colony formation of freshly isolated leukemic blasts from six to eight T-lineage ALL patients with a mean plating efficiency of 196 +/- 53 (background subtracted) colonies/10(5) blasts plated. Stimulation of T-lineage ALL blasts with rhIL-7 resulted in markedly enhanced tyrosine phosphorylation of six distinct phosphoproteins with molecular weights of 57, 72, 98, 123, 150, and 190 Kd, and induced a rapid increase in the production of inositol-1,4,5-trisphosphate (Ins-1,4,5-P3), which was inhibitable by the tyrosine-specific protein kinase inhibitor genistein, but not by the serine/threonine-specific protein kinase C inhibitor H7. Similarly, rhIL-7 stimulated Ins-1,4,5-P3 production in CEM-1.3 T-lineage ALL cells and this stimulation was inhibitable by the tyrosine-specific protein kinase inhibitors genistein and herbimycin A, but not by H-7. Thus, the transmembrane signal triggered by engagement of the IL-7R is intimately linked to a functional tyrosine-specific protein kinase pathway and stimulates the phosphoinositide (PI) turnover and proliferation of T-lineage ALL blasts. The presented data confirm and extend previous studies on the expression of functional IL-7R on T- lineage ALL blasts and support the hypothesis that IL-7 may play an important regulatory role in the biology of T-lineage ALL.

Download Full-text

Engagement of interleukin-7 receptor stimulates tyrosine phosphorylation, phosphoinositide turnover, and clonal proliferation of human T-lineage acute lymphoblastic leukemia cells

Blood ◽

10.1182/blood.v78.3.564.bloodjournal783564 ◽

1991 ◽

Vol 78 (3) ◽

pp. 564-570

Author(s):

I Dibirdik ◽

MC Langlie ◽

JA Ledbetter ◽

L Tuel-Ahlgren ◽

V Obuz ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Protein Kinase ◽

Tyrosine Phosphorylation ◽

Kinase Inhibitor ◽

Lymphoblastic Leukemia ◽

Specific Protein ◽

Protein Kinase Inhibitors ◽

In Vitro Proliferation ◽

Interleukin 7 ◽

Specific Protein Kinase

The purposes of this study were to examine the biologic effects of the engagement of the interleukin-7 receptor (IL-7R) with recombinant human interleukin-7 (rhIL-7) in immunophenotypically distinct T-lineage acute lymphoblastic leukemia (ALL) blasts and to elucidate the biochemical nature of the IL-7R-linked transmembrane signal in rhIL-7-responsive T- lineage ALL blast populations. In the absence of costimulants, rhIL-7 stimulated the in vitro proliferation and colony formation of freshly isolated leukemic blasts from six to eight T-lineage ALL patients with a mean plating efficiency of 196 +/- 53 (background subtracted) colonies/10(5) blasts plated. Stimulation of T-lineage ALL blasts with rhIL-7 resulted in markedly enhanced tyrosine phosphorylation of six distinct phosphoproteins with molecular weights of 57, 72, 98, 123, 150, and 190 Kd, and induced a rapid increase in the production of inositol-1,4,5-trisphosphate (Ins-1,4,5-P3), which was inhibitable by the tyrosine-specific protein kinase inhibitor genistein, but not by the serine/threonine-specific protein kinase C inhibitor H7. Similarly, rhIL-7 stimulated Ins-1,4,5-P3 production in CEM-1.3 T-lineage ALL cells and this stimulation was inhibitable by the tyrosine-specific protein kinase inhibitors genistein and herbimycin A, but not by H-7. Thus, the transmembrane signal triggered by engagement of the IL-7R is intimately linked to a functional tyrosine-specific protein kinase pathway and stimulates the phosphoinositide (PI) turnover and proliferation of T-lineage ALL blasts. The presented data confirm and extend previous studies on the expression of functional IL-7R on T- lineage ALL blasts and support the hypothesis that IL-7 may play an important regulatory role in the biology of T-lineage ALL.

Download Full-text