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)

The interaction of cells with components of the extracellular matrix through their integrin receptors results in the stimulation of tyrosine phosphorylation of several proteins, suggesting that these receptors play a key role in signal transduction. Here we report that antibody-mediated ligation and clustering of alpha 3 beta 1 and alpha 6 beta 1/alpha 6 beta 4 integrins resulted in the stimulation of tyrosine phosphorylation of proteins that are specific for each heterodimer. Thus, ligation and clustering of the alpha 3 beta 1 integrin on human prostate carcinoma cells (PC-3) and human umbilical vein endothelial cells (HUVEC) with anti-alpha 3 antibodies resulted in the stimulation of tyrosine phosphorylation of a 55 kDa protein. In contrast, ligation and clustering of the alpha 6 beta 1 integrin on these cells with anti-alpha 6 antibody resulted in the dramatic stimulation of tyrosine phosphorylation of a 90 kDa protein in addition to a 52 kDa protein, and ligation and clustering of alpha 5 beta 1 on HUVEC did not result in the apparent stimulation of tyrosine phosphorylation of any proteins. Clustering with anti-beta 1 antibodies triggered the tyrosine phosphorylation of all of these proteins, whereas ligation and clustering of PC-3 cells with an anti-beta 4 antibody resulted in the tyrosine phosphorylation of a distinct 62 kDa protein. Since the PC-3 cells express both alpha 6 beta 1 and alpha 6 beta 4, these data suggest that these two receptors can transduce distinct signals. All of the phosphorylations could be inhibited by treating the cells with Genistein, a tyrosine kinase inhibitor. Antibody-mediated ligation and clustering of integrins on the two types of cells did not result in the stimulation of tyrosine phosphorylation of pp125 focal adhesion kinase, although this was observed upon cell attachment and spreading on fibronectin, laminin and anti-alpha 3 monoclonal antibody. Collectively, these data demonstrate that cross-linking of different integrin heterodimers can stimulate tyrosine kinase activities, leading to the phosphorylation of distinct proteins, which are also different from those observed when cells are allowed to spread on a matrix.
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PMID:Stimulation of tyrosine phosphorylation of distinct proteins in response to antibody-mediated ligation and clustering of alpha 3 and alpha 6 integrins. 762 2

pp125FAK, a protein tyrosine kinase (PTK) co-localized with integrins in focal adhesion plaques, is known to transduce signals involved in the regulation of cell adhesion and motility as well as the anchorage-independent growth of transformed cells. We investigated whether pp125FAK could be part of a signalling pathway that contributes to the progression of human prostate carcinoma (PCa). Up-regulation of pp125FAK expression, its activation by phosphorylation on tyrosine and its association with paxillin and p50csk were preferentially observed in PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues showed undetectable or low levels of both FAK mRNA and protein and an absence of pp125FAK signalling complexes. The increase in expression and activation of pp125FAK in metastatic PCa tissues was also corroborated by our findings in human PCa cell lines. Indeed, higher levels of pp125FAK and FAK mRNA were observed in highly tumorigenic PC-3 cells as was the presence of activated pp125FAK, as opposed to an inactive form in LNCaP cells, which have a lower tumorigenic ability. In addition, pp125FAK formed signalling complexes with both paxillin and p50csk in PC-3 cells as in metastatic PCa tissues. Together, our results show that an increase in FAK mRNA and protein, as well as pp125FAK activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.
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PMID:Focal adhesion kinase (pp125FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma. 890 Apr 22

Bombesin-like peptides, including the mammalian homologue gastrin-releasing peptides, are highly expressed and secreted by neuroendocrine cells in prostate carcinoma (PCa) tissues and are likely to be related to the progression of this disease. In the present study, we show that bombesin enhances the migration of androgen-independent PCa cells (PC-3) in vitro, while not affecting their adhesion to extracellular matrix proteins. The bombesin-increased motility of PC-3 cells occurs through its receptor, and, as shown with inhibitors, it likely requires activation of both protein tyrosine kinases (PTKs) and protein kinases C (PKCs). Because the focal adhesion kinase pp125FAK plays a key role in adhesion/motility and is highly expressed in advanced PCa, we examined whether in PC-3 cells bombesin signal transduction triggers the tyrosine phosphorylation of this PTK and of associated integrins and signaling proteins likely to be present in focal adhesion plaques. pp125FAK tyrosine phosphorylation was stimulated by bombesin and mimicked by PKC activation with the tumor-promotor phorbol 12-myristate-13-acetate (PMA). Moreover, this effect of bombesin on pp125FAK tyrosine phosphorylation requires the presence of both active PKC and cytoskeleton integrity since this signal was abolished by down-regulating PKCs induced by prolonged PMA treatment or by PKC inhibition with GF 109203X, as well as by disruption of the cytoskeleton with cytochalasin D. We also show that bombesin increases the tyrosine phosphorylation of a 95-kDa protein (pp95) which was co-immunoprecipitated with the alpha v and beta (3 and 5) subunits, forming integrin receptors with alpha v in PC-3 cells. The protein pp95 is distinct from the endogenously tyrosine-phosphorylated beta3 subunit. In addition, upon bombesin treatment, the beta1, beta3 and beta5 integrin subunits co-immunoprecipitated with pp125FAK and major phosphotyrosine (pY)-containing proteins of 125 and 68-70 kDa, likely corresponding to pp125FAK and paxillin. Together our data suggest that, in addition to PKC activation, tyrosine phosphorylation of pp125FAK and integrin-associated proteins may play an important role in bombesin signaling, triggering the processes of PCa cell motility and invasion.
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PMID:Bombesin stimulates the motility of human prostate-carcinoma cells through tyrosine phosphorylation of focal adhesion kinase and of integrin-associated proteins. 924 95

Calpain is a calcium-dependent cysteine protease that is implicated in calcium-dependent cell death, and calpain inhibitors are generally considered as inhibitors of apoptosis. To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target cell lines were killed by CPI-2, including: ALL-1, a multidrug-resistant BCR-ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highly radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pre-pre B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell lines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT-40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyrosine kinases LYN or BTK. Notably, caspase inhibitor I effectively inhibited CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-susceptible protease results in caspase activation, leading to apoptosis in ALL/NHL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid leukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell lines BT-20/breast cancer, PC-3/prostate cancer, U373/glioblastoma, and HeLa/epitheloid cancer, were not susceptible to the cytotoxicity of CPI-2. Taken together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising new class of antileukemia/lymphoma agents that deserves further development.
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PMID:Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells. 1087 99

Prostate cancer is the second most common cause of cancer deaths among men in the United States. We have investigated the effect of cyclo-(Arg-Gly-Asp-D-Phe-Val; cRGDfV), Arg-Gly-Asp, or Arg-Gly-Asp-Ser, on survival of human prostate cancer (LNCaP and PC-3) and normal (HEL) cells in vitro. Addition of cRGDfV (20 microg/ml) but not the linear Arg-Gly-Asp or Arg-Gly-Asp-Ser peptide induced significant (approximately 84%) killing of LNCaP cells expressing alphavbeta3 integrins on their surfaces. In contrast, none of these peptides had any major effect on the growth of PC-3 or HEL cells, which express little alphavbeta3 integrin on their surfaces. Treatment of LNCaP but not of PC-3 or HEL cells with cRGDfV resulted in cleavage of focal adhesion kinase, a key player in integrin-mediated signal transduction pathway. The evidence we present here suggests that the killing of LNCaP cells after cRGDfV treatment was attributable to apoptosis or programmed cell death. This is evidenced by activation of at least two caspases (caspase-3 and caspase-9) as detected by cleavage of poly(ADP-ribose) polymerase and partial blocking of apoptosis by a selective inhibitor of caspase-9. Our results suggest that cRGDfV may be an effective treatment for some human prostate cancers by inducing apoptosis through interference with the regulation of integrin/focal adhesion kinase-mediated signal transduction pathway necessary for cell survival.
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PMID:Induction of apoptosis of integrin-expressing human prostate cancer cells by cyclic Arg-Gly-Asp peptides. 1159 88

In cloning tyrosine kinase genes in dog prostate cells, a fragment of the vascular endothelial growth factor (VEGF) receptor 1 or Flt-1 was sequenced. To test for a functional protein, Flt-1 antibodies were used to probe immunoprecipitated tyrosine phosphorylated proteins. Western blotting revealed a major 170-180 kDa band and a few bands below 116 kDa in dog prostate and human prostatic carcinoma PC-3 cells, with higher levels in PC-3. Similar results were obtained with human placental membranes used as a source of Flt-1. That the major Flt-1 tyrosine phosphorylated protein was likely VEGF-R1 and part of VEGF signaling pathways was shown by enhanced level of only this protein when PC-3 cells were exposed to VEGF. Accordingly specific cell surface receptor complexes, displaced by VEGF but not EGF and compatible with Flt-1 in size, were revealed by chemical cross-linking after 125I-VEGF binding. Similarly to the prostatic neuroproduct, gastrin-releasing peptide/bombesin, VEGF directly triggered the tyrosine phosphorylation of focal adhesion kinase and stimulated PC-3 cell motility. The titration of prostate tissue sections with VEGF-A antibodies revealed a confined staining in chromogranin A and/or serotonin positive neuroendocrine (NE) cells, including in primary tumors and lymph node metastases. Given that NE differentiation is associated with advanced disease, that NE cells are a significant source of VEGF in prostatic tumors, and that VEGF directly act on prostate cancer cells in vitro, VEGF-A may be more than angiogenic in prostate cancer and hence favor progression by affecting tumor cells.
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PMID:Vascular endothelial growth factor and signaling in the prostate: more than angiogenesis. 1203 75

Lysophosphatidic acid (LPA) is a lipid mediator that may play an important role in growth and survival of carcinomas. In this study, LPA production and response were characterized in two human prostate cancer (CaP) cell lines: PC-3 and Du145. Bombesin, a neuroendocrine peptide that is mitogenic for CaP cells, stimulated focal adhesion kinase phosphorylation and activated the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. Similar responses were elicited by 18:1 LPA (oleoyl-LPA). Studies using radioisotopic labeling revealed that both PC-3 and Du145 generate LPA and that LPA production is increased by bombesin. The kinetics of bombesin-induced phospholipase D activation and LPA production were similar. Using electrospray ionization mass spectrometry, 18:1 LPA was found to be an abundant LPA species in CaP cell medium. Structure activity studies of acyl-LPAs revealed that 18:1 LPA is most efficacious for activation of extracellular signal-regulated kinase and phospholipase D in CaP cells. Incubation with 18:1 LPA caused homologous desensitization of LPA response, whereas bombesin caused heterologous desensitization. LPA was present at nanomolar levels in medium from bombesin-treated cells. LPA extracted from the medium induced calcium mobilization in CaP cells. These results demonstrate that bioactive LPA is generated by CaP cells in response to a mitogen and suggest that 18:1 LPA can act as an autocrine mediator.
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PMID:Role for 18:1 lysophosphatidic acid as an autocrine mediator in prostate cancer cells. 1208 19

Genetic alterations and/or deletion of the tumor suppressor gene PTEN/MMAC/TEP1 occur in many types of human cancer including prostate cancer. We describe the production of monoclonal antibody against recombinant human PTEN and the study of PTEN gene and protein expression in three commercially available human prostate cancer cell lines, PC-3, LNCaP, and DU 145. Northern blotting analyses showed that LNCaP and DU145 but not PC-3 cells expressed PTEN mRNA. However, Western blotting analyses using a monoclonal antibody against PTEN demonstrated the expression of PTEN protein in DU145 but not LNCaP cells. In DU 145 cells, PTEN expression at both the mRNA and protein levels inversely correlated with serum concentrations and levels of PKB/Akt phosphorylation. In addition, the basal activity of PKB/Akt as indicated by level of phosphorylation was higher in prostate cancer cells which do not express PTEN than that in the cells expressing wild type PTEN. Thus, PTEN may play a critical role in regulating cellular signaling in prostate cancer cells.
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PMID:Downregulation of PTEN/MMAC/TEP1 expression in human prostate cancer cell line DU145 by growth stimuli. 1219 Jan 24

We have previously reported that interleukin 10 (IL-10) signalling stimulated activation of a specific enhancer element, termed HTE-1, to promote tissue inhibitor of matrix metalloproteinase1 (TIMP-1) expression in human bone metastatic PC-3 subclone (PC-3 ML) cells. Recently, we have identified an IL-10 responsive signal molecule, termed IL-10E1, which binds the HTE-1 element and cloned the gene encoding for the 22 kDa protein. In this paper, we have examined the mechanism of IL-10/IL-10 receptor signalling in two distinct human prostate cell lines, a 'normal' prostate epithelial cell line, termed NPTX-1532 and highly metastatic PC-3 ML tumour cells. Signalling cascade studies revealed that IL-10 stimulated tyrosine phosphorylation of JAK1 and TYK2 receptor kinases and tyrosine phosphorylation of IL-10E1. Phosphorylation, triggered IL-10E1's rapid translocation to the nucleus by 10-30 min. Deletion analysis combined with transient transfection experiments revealed that the n-terminal domain (approximately 74 a.a.) of the IL-10E1 protein, the nt-nls peptide, was stimulated by IL-10 to translocate to the nucleus and induce TIMP-1 expression. Site-directed mutagenesis further showed that phosphorylation of two tyrosine moieties (Y57 and Y62) of the nt-nls peptide was required for IL-10 activation of signalling and TIMP-1 expression. The data demonstrate, for the first time, that IL-10 receptor signalling of TIMP-1 expression is regulated by tyrosine phosphorylation of a novel gene, IL-10E1, in human prostate cells.
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PMID:A novel IL-10 signalling mechanism regulates TIMP-1 expression in human prostate tumour cells. 1458 88

Cannabinoids exert a variety of physiological and pharmacological responses in humans through interaction with specific cannabinoid receptors. Cannabinoid receptors described to date belong to the seven-transmembrane-domain receptor superfamily and are coupled through the inhibitory G(i) protein to adenylyl cyclase inhibition. However, downstream signal transduction mechanisms triggered by cannabinoids are poorly understood. We examined here the involvement of the phosphoinositide 3-kinase (PI3K)/PKB pathway in the mechanism of action of cannabinoids in human prostate epithelial PC-3 cells. Cannabinoid receptors CB(1) and CB(2) are expressed in these cells, as shown by RT-PCR, Western blot and immunofluorescence techniques. Treatment of PC-3 cells with either Delta(9)-tetrahydrocannabinol (THC), the major psychoactive ingredient of marijuana, or R-(+)-methanandamide (MET), an analogue of the endogenous cannabinoid anandamide, increased phosphorylation of PKB in Thr308 and Ser473. The stimulation of PKB induced by cannabinoids was blocked by the two cannabinoid receptor antagonists, SR 141716 and SR 144528, and by the PI3K inhibitor LY 294002. These results indicate that activation of cannabinoid receptors in PC-3 cells stimulate the PI3K/PKB pathway. We further investigated the involvement of Raf-1/Erk activation in the mechanism of action of cannabinoid receptors. THC and MET induced translocation of Raf-1 to the membrane and phosphorylation of p44/42 Erk kinase, which was reversed by cannabinoid receptor antagonists and PI3K inhibitor. These results point to a sequential connection between cannabinoid receptors/PI3K/PKB pathway and Raf-1/Erk in prostate PC-3 cells. We also show that this pathway is involved in the mechanism of NGF induction exerted by cannabinoids in PC-3 cells.
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PMID:Activation of phosphoinositide 3-kinase/PKB pathway by CB(1) and CB(2) cannabinoid receptors expressed in prostate PC-3 cells. Involvement in Raf-1 stimulation and NGF induction. 1283 10


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