Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SH-SY5Y neuroblastoma cells are a well-characterized model for studying the induction of neuronal differentiation. TPA treatment of these cells induces cytoskeletal rearrangements that ultimately result in neurite extension. However, the signaling pathways that precede these changes are poorly understood. Other investigators have shown that TPA treatment of SH-SY5Y cells results in increased tyrosine phosphorylation of cytoskeletal-associated proteins, including the adapter protein Cas. In this report, we examine the events upstream and downstream of Cas phosphorylation. We show that TPA treatment induces the PKC-dependent association of tyrosine-phosphorylated Cas with Crk. The activity of two protein tyrosine kinases, Src and FAK, was shown to be necessary and sufficient for TPA-induced Cas phosphorylation. We propose that the PKC-dependent phosphorylation of Cas by Src and FAK promotes the establishment of Cas-Crk complexes and that these interactions may play an important role in regulating the actin cytoskeleton during neuronal differentiation.
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PMID:PKC-dependent activation of FAK and src induces tyrosine phosphorylation of Cas and formation of Cas-Crk complexes. 1126 86

Nitric oxide (NO) can participate in cellular signaling. In this study, monoclonal antibodies against proteins from the growth factor-mediated signalling pathway were used to identify a set of 126-, 56-, 43-, and 40-kDa proteins phosphorylated on tyrosine at NO stimulation of murine fibroblasts overexpressing the human epidermal growth factor receptor. The band corresponding to the 126-kDa protein was FAK. The 56-kDa protein was Src kinase, and the doublet 43- and 40-kDa protein corresponded to the extracellular-regulated MAP kinases (ERK1/ERK2). The effects of NO on focal adhesion complexes were also investigated. FAK was constitutively associated with the adapter protein Grb2 in HER14 cells. Treatment of the cells with the NO donor, sodium nitroprusside, or with EGF did not change this association. We also detected a basal constitutive association of Src kinase with FAK in HER14 cells. In NO-treated cells, this association was stimulated. The doublet 43/40-kDa protein was identical to the ERK1/ERK2 MAP kinases. NO stimulated an increase in ERK1/ERK2 phosphorylation as assessed by a shift in its eletrophoretic mobility and by increased phosphotyrosine immunoreactivity. Furthermore, NO-dependent activation of ERK1/ERK2 depended on the intracellular redox status. Inhibition of glutathione synthesis was necessary to promote activation of the kinases.
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PMID:Nitric oxide stimulates tyrosine phosphorylation of focal adhesion kinase, Src kinase, and mitogen-activated protein kinases in murine fibroblasts. 1128 Dec 84

Paxillin is a focal adhesion adapter protein involved in integrin signaling. Paxillin LD motifs bind several focal adhesion proteins including the focal adhesion kinase, vinculin, the Arf-GTPase-activating protein paxillin-kinase linker, and the newly identified actin-binding protein actopaxin. Microsequencing of peptides derived from a 50-kDa paxillin LD1 motif-binding protein revealed 100% identity with integrin-linked kinase (ILK)-1, a serine/threonine kinase that has been implicated in integrin, growth factor, and Wnt signaling pathways. Cloning of ILK from rat smooth muscle cells generated a cDNA that exhibited 99.6% identity at the amino acid level with human ILK-1. A monoclonal antibody raised against a region of the carboxyl terminus of ILK, which is identical in rat and human ILK-1 protein, recognized a 50-kDa protein in all cultured cells and tissues examined. Binding experiments showed that ILK binds directly to the paxillin LD1 motif in vitro. Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ILK occurs in vivo in both adherent cells and cells in suspension. Immunofluorescence microscopy of fibroblasts demonstrated that endogenous ILK as well as transfected green fluorescent protein-ILK co-localizes with paxillin in focal adhesions. Analysis of the deduced amino acid sequence of ILK identified a paxillin-binding subdomain in the carboxyl terminus of ILK. In contrast to wild-type ILK, paxillin-binding subdomain mutants of ILK were unable to bind to the paxillin LD1 motif in vitro and failed to localize to focal adhesions. Thus, paxillin binding is necessary for efficient focal adhesion targeting of ILK and may therefore impact the role of ILK in integrin-mediated signal transduction events.
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PMID:Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions. 1130 46

The alkylating agent methylmethanesulfonate (MMS) activates the c-jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and the p38 mitogen-activated protein kinase (p38MAPK) pathways via different mechanisms of action. Activation of p38MAPK by MMS involves the pp125 focal adhesion kinase-related tyrosine kinase RAFTK and the MAPK kinase 3. The way in which MMS can activate JNK/SAPK has not been elucidated. Here we describe the identification by differential display of human mitogen-activated gene-6 (MIG-6) as a novel MMS-inducible gene. Induction of MIG-6 by MMS was found in human diploid skin fibroblasts and in simian virus 40-transformed skin fibroblasts, indicating that the enhanced expression of MIG-6 after MMS-treatment did not require p53. The signal leading to activation of MIG-6 appeared to be independent of DNA damage. High MIG-6 expression was found in the liver, lung, and placenta. MIG-6 is an adapter protein that binds to the activated form of cdc42Hs and to 14-3-3 proteins, thereby activating JNK/SAPKs. Our results suggest that activation of JNK/SAPKs by MMS may involve the induction of MIG-6.
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PMID:Induction of the SAPK activator MIG-6 by the alkylating agent methyl methanesulfonate. 1142 82

In addition to engagement of the T cell receptor-CD3 complex, T lymphocytes can be activated by a variety of cell surface molecules including the approximately 50-kDa surface receptor CD2. While the majority of biochemical signaling elements are triggered by either CD2 or TcR-CD3 receptors, a small number of proteins are engaged by only one receptor. Recently, p62(dok) (Dok1), a member of the Dok family of adapter molecules, has been reported to be activated by CD2 and not by CD3 engagement. Here we have examined the role of p62(dok) in CD2-dependent signaling in Jurkat T cells. As previously reported, we find that ligation of the CD2 molecule by mitogenic pairs of anti-CD2 mAbs led to phosphorylation of p62(dok). While CD2-induced p62(dok) tyrosine phosphorylation was independent of both the p36/38 membrane adapter protein linker of activated T cells (LAT) and the ZAP70/Syk family of kinases, it was dependent upon the Src family of kinases including Lck and Fyn. We find further that CD2 engagement induced the association of tyrosine-phosphorylated p62(dok) to Crk-L. The CD2-dependent association of p62(dok) to Crk-L was independent of expression of the ZAP70/Syk family of kinases. Of note, while T cell receptor-CD3 engagement did not induce either p62(dok) phosphorylation or Crk-L association in Jurkat T cells, it did inhibit CD2-dependent p62(dok)-Crk-L complexes; this TcR-CD3-mediated regulation was dependent upon ZAP70 kinase activity. Our data suggest that phosphorylation of p62(dok) and its interaction with other signaling proteins may depend upon integrated signals emanating from the CD2 receptor, utilizing a ZAP70/LAT-independent pathway, and the TcR-CD3 receptor, which is ZAP70/Syk-dependent.
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PMID:T cell regulation of p62(dok) (Dok1) association with Crk-L. 1155 20

Phosphoprotein associated with GEMs (PAG), also known as Csk-binding protein (Cbp), is a broadly expressed palmitoylated transmembrane adapter protein found in membrane rafts, also called GEMs (glycosphingolipid-enriched membrane microdomains). PAG is known to bind and activate the essential regulator of Src-family kinases, cytoplasmic protein tyrosine kinase Csk. In the present study we used the yeast 2-hybrid system to search for additional proteins which might bind to PAG. We have identified the abundant cytoplasmic adapter protein EBP50 (ezrin/radixin/moesin (ERM)-binding phosphoprotein of 50 kDa), also known as NHERF (Na(+)/H(+) exchanger regulatory factor), as a specific PAG-binding partner. The interaction involves the C-terminal sequence (TRL) of PAG and N-terminal PDZ domain(s) of EBP50. As EBP50 is known to interact via its C-terminal domain with the ERM-family proteins, which in turn bind to actin cytoskeleton, the PAG-EBP50 interaction may be important for connecting membrane rafts to the actin cytoskeleton.
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PMID:Interaction between two adapter proteins, PAG and EBP50: a possible link between membrane rafts and actin cytoskeleton. 1168 85

We isolated a cDNA clone encoding a novel Src homology (SH)2 domain-containing protein of 47 kDa from a human cDNA library. As its transcript was predominantly expressed in hematopoietic cells, this gene was termed HSH2 for hematopoietic SH2 protein. This protein contains several putative protein-binding motifs, SH3-binding proline-rich regions, and phosphotyrosine sites, but lacks enzymatic motifs. In a yeast two-hybrid screen, we identified a cytokine-regulated tyrosine kinase c-FES and an activated Cdc42-associated tyrosine kinase ACK1 as HSH2 interactors. HSH2 bound c-FES via its C-terminal region as well as its N-terminal region including the SH2 domain, whereas it bound ACK1 via its N-terminal proline-rich region. Furthermore, these two kinases bound and tyrosine-phosphorylated HSH2 in mammalian cells. Hence, we postulate that HSH2 functions as an adapter protein involved in tyrosine kinase signaling, and possibly regulates cytokine signaling and cytoskeletal reorganization, in hematopoietic cells.
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PMID:HSH2: a novel SH2 domain-containing adapter protein involved in tyrosine kinase signaling in hematopoietic cells. 1170 21

The Src homology 2 (SH2) domain-containing protein SH2-Bbeta binds to and is a substrate of the growth hormone (GH) and cytokine receptor-associated tyrosine kinase JAK2. SH2-Bbeta also binds, via its SH2 domain, to multiple activated growth factor receptor tyrosine kinases. We have previously implicated SH2-Bbeta in GH and platelet-derived growth factor regulation of the actin cytoskeleton. We extend these findings by establishing a potentiating effect of SH2-Bbeta on GH-dependent cell motility and defining regions of SH2-Bbeta required for this potentiation. Time-lapse video microscopy, phagokinetic, and/or wounding assays demonstrate reduced movement of cells overexpressing SH2-Bbeta lacking an intact SH2 domain because of a point mutation or a C-terminal truncation. An N-terminal proline-rich domain (amino acids 85-106) of SH2-Bbeta is required for inhibition of cellular motility by SH2 domain-deficient mutants. Co-immunoprecipitation experiments indicate that Rac binds to this domain. GH is shown to activate endogenous Rac, and dominant negative mutants of SH2-Bbeta are shown to inhibit membrane ruffling induced by constitutively active Rac. These findings suggest that SH2-Bbeta is an adapter protein that facilitates actin rearrangement and cellular motility by recruiting Rac and potentially Rac-regulating, Rac effector, or other actin-regulating proteins to activated cytokine (e.g. GH) and growth factor receptors.
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PMID:SH2-Bbeta is a Rac-binding protein that regulates cell motility. 1178 45

Activation of T lymphocytes requires the engagement of the T-cell receptor and costimulation molecules through cell-to-cell contacts. The tetraspanin CD82 has previously been shown to act as a cytoskeleton-dependent costimulation molecule. We show here that CD82 engagement leads to the tyrosine phosphorylation and association of both the Rho GTPases guanosine exchange factor Vav1 and adapter protein SLP76, suggesting that Rho GTPases participate in CD82 signaling. Indeed, broad inactivation of all Rho GTPases, or a specific blockade of RhoA, Rac1 or Cdc42, inhibited the morphological changes linked to CD82 engagement but failed to modulate the inducible association of CD82 with the actin network. Rho GTPase inactivation, as well as actin depolymerization, reduced the ability of CD82 to phosphorylate Vav and SLP76 and to potentiate the phosphorylation of two early TcR signaling intermediates: the tyrosine kinases ZAP70 and membrane adapter LAT. Taken together, this suggests that an amplification loop, via early Vav and SLP76 phosphorylations and Rho-GTPases activation, is initiated by CD82 association with the cytoskeleton, which permits cytoskeletal rearrangements and costimulatory activity. Moreover, the involvement of CD82 in the formation of the immunological synapse is strongly suggested by its accumulation at the site of TcR engagement. This novel link between a tetraspanin and the Rho GTPase cascade could explain why tetraspanins, which are known to form heterocomplexes, are involved in cell activation, adhesion, growth and metastasis.
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PMID:Rho GTPases link cytoskeletal rearrangements and activation processes induced via the tetraspanin CD82 in T lymphocytes. 1183 93

Tumor necrosis factor-alpha (TNFalpha, 10-100 ng/ml) provokes a dramatic cell death in differentiated PC12 cells (dPC12), but it does not affect the viability and the proliferation of naive PC12 cells (nPC12). We have analyzed the molecular alterations of the TNFalpha-signal cascade underlying this developmental switch toward propagation of apoptosis. The transcriptional inhibitor actinomycin D rendered nPC12 responsive for TNFalpha-induced death, but was hardly effective in dPC12, suggesting that TNFalpha evokes its harmful action in dPC12 predominantly by posttranslational modification of existing molecules. This suggestion was supported by the finding that differentiation of PC12 per se went along with the increased expression of the proapoptotic TNFalpha-receptor I (p55) and its adapter protein Traf-2, whereas expression and phosphorylation of the antiapoptotic Akt (PKB) declined. We could demonstrate that the c-Jun N-terminal kinases (JNKs) mediate this enhanced capacity of apoptotic signaling in dPC12. TNFalpha induced in dPC12, but not nPC12, a biphasic activation of JNKs with a rapid transient JNK1 activation and a second persistent activation of JNK1 and JNK2 paralleled by phosphorylation of c-Jun; in contrast, TNFalpha did not activate p38 kinase. Block of JNKs by CEP-11004, a MLK antagonist and subsequently indirect inhibitor of JNK activation, or L-JNK11, a direct peptidergic inhibitor of JNK activity, almost completely rescued dPC12. Summarizing, the NGF-triggered formation of neurites during differentiation of PC12 includes the reinforced propensity for apoptosis, with JNK2 as the effector in JNK3-negative PC12. These findings offer novel insights into the increased risk of neuronal death, which is linked to the potential to regenerate.
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PMID:Fatal shift of signal transduction is an integral part of neuronal differentiation: JNKs realize TNFalpha-mediated apoptosis in neuronlike, but not naive, PC12 cells. 1209 55


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