Disease relevance of PTK2

• PTK2 and EIF3S3 genes may be amplification targets at 8q23-q24 and are associated with large hepatocellular carcinomas [1].
• When we analyzed potential relationships between elevated expression of PTK2 and EIF3S3 and clinicopathologic parameters, high expression of the 2 transcripts was significantly associated with large (>5 cm) tumor size and with hepatitis B virus (HBV) infection [1].
• In this study, FAK protein expression and mRNA were detected in 25 of 60 cases (42%) of acute myeloid leukemia (AML) [2].
• Furthermore, C8161 melanoma cells with endogenous CD151 were also shown to respond to homophilic CD151 interactions for the induction of adhesion-dependent activation of FAK, Src, and c-Jun [3].
• Thus, FAK may act in glioblastoma as a downstream target of growth factor signaling, with integrins enhancing the impact of such signaling in the tumor microenvironment [4].

High impact information on PTK2

• Further, HHV-8 infection induced the integrin-mediated activation of focal adhesion kinase (FAK) [5].
• Overexpression of FAK partially antagonized the effects of PTEN [6].
• Aggregation of integrins by noninhibitory monoclonal antibodies on beads induced intracellular accumulations of pp125FAK and tensin, as well as phosphorylation, but no accumulation of other cytoskeletal proteins such as talin [7].
• As both FAK and Src catalytic activities are important in promoting VEGF-associated tumor angiogenesis and protease-associated tumor metastasis, support is growing that FAK and Src may be therapeutically relevant targets in the inhibition of tumor progression [8].
• Integrins can alter cellular behavior through the recruitment and activation of signaling proteins such as non-receptor tyrosine kinases including focal adhesion kinase (FAK) and c-Src that form a dual kinase complex [8].

Chemical compound and disease context of PTK2

• KSHV envelope glycoprotein gB induces the FAK-Src-PI3K-RhoGTPase (where FAK is focal adhesion kinase) signaling pathway [9].
• Focal adhesion kinase and protein kinase B cooperate to suppress Doxorubicin-induced apoptosis of breast tumor cells [10].
• Garcinol modulates tyrosine phosphorylation of FAK and subsequently induces apoptosis through down-regulation of Src, ERK, and Akt survival signaling in human colon cancer cells [11].
• Nitric oxide, which is produced in metastases by three different NOS isozymes is capable of antagonizing the binding of FAK to matrix integrins [12].
• Human cytomegalovirus US28-mediated SMC migration is inhibited by treatment with PP2 and through the expression of either of two dominant negative inhibitors of FAK (F397Y and NH2-terminal amino acids 1-401) [13].

Biological context of PTK2

• On the basis of synteny of mouse and human chromosomal maps, the position of the human PTK2 gene probably corresponds to human Chr 8q24-qter [14].
• FAK integrates growth-factor and integrin signals to promote cell migration [15].
• RESULTS: HSC adhesion to extracellular matrix components (collagen type I and IV, laminin, and fibronectin) and antibody-mediated beta 1 ligation elicited increased tyrosine phosphorylation of FAK [16].
• Abrogation of SHP-2 catalytic activity with a dominant-negative mutant (SHP2-C>S) abolishes IGF-I-induced FAK dephosphorylation, and cells expressing SHP2-C>S show reduced IGF-I-stimulated chemotaxis compared with either mock- or SHP-2 wild-type-transfected cells [17].
• Emphasis will also be placed on the role of FAK in generating cell survival signals and the cleavage of FAK during caspase-mediated apoptosis [18].

Anatomical context of PTK2

• In conclusion, PTK2 and EIF3S3, which, respectively, encode focal adhesion kinase and the p40 subunit of the eukaryotic initiation factor 3, were probable targets within the amplification at 8q23-q24 and may be involved in progression of HCC [1].
• The human homolog (PTK2) has been assigned to human Chr 8 on a panel of somatic hybrid cell lines [14].
• Overexpression of dominant-negative FAK, FRNK, along with CIB in CHO cells completely inhibits CIB-induced cell migration [19].
• Similar to FAK, dephosphorylation of RAFTK was observed when adherent transfected COS cells were detached [20].
• Coexpression of RAFTK and FAK proteins in megakaryocytic cells and blood platelets was observed [20].

Associations of PTK2 with chemical compounds

• Our results establish that FAK is an important receptor-proximal link between growth-factor-receptor and integrin signalling pathways [15].
• The size of aggregates formed at a high shear rate in the presence of 2B-rVWF was decreased by genistein, demonstrating the biologic relevance of pp125FAK [21].
• In contrast, neither RGDS peptide nor MoAb 7E3, both known to block alphaIIbbeta3 engagement, had any effect on SIPA and pp125FAK [21].
• FAK+ AML cells displayed significantly higher migration capacities and resistance to daunorubicin, compared with FAK- cells [2].
• Focal adhesion kinase (FAK) is phosphorylated on tyrosine and serine residues after cell activation [22].

Physical interactions of PTK2

• Focal adhesion kinase interacts with the transcriptional coactivator FHL2 and both are overexpressed in epithelial ovarian cancer [23].
• In addition, pp125FAK formed signalling complexes with both paxillin and p50csk in PC-3 cells as in metastatic PCa tissues [24].
• PI 3-kinase has also been shown to bind FAK in a cell adhesion-dependent manner at the major autophosphorylation site Y397 [25].
• The results demonstrate that tyrosine-phosphorylated pp125FAK directly interacts with the SH2 domain of Grb2 [26].
• The PTEN trapping mutant D92A bound wild-type FAK, requiring FAK autophosphorylation site Tyr397 [27].

Enzymatic interactions of PTK2

• The tumor suppressor PTEN dephosphorylates focal adhesion kinase (FAK) and inhibits integrin-mediated cell spreading and cell migration [28].
• RESULTS: Immunoprecipitated, mutant RET from cells or the recombinant RET kinase domain was able to directly phosphorylate tyrosine residues on FAK [29].
• Focal adhesion kinase (FAK) becomes activated and tyrosine-phosphorylated in response to cell adhesion to extracellular matrix proteins in a variety of cell types, and associates with a number of signaling molecules, structural proteins, and beta integrin cytoplasmic domains [30].
• However, Hic-5 is not tyrosine phosphorylated either by the coexpressed FAK in COS cells or by integrin stimulation in 293T cells [31].
• Immunoprecipitation and anti-phosphotyrosine immunoblotting were carried out to detect the phosphorylated FAK and phosphorylated paxillin contents of the IGF-I-treated and untreated trophoblast cells [32].

Co-localisations of PTK2

• A fraction of Nck-2 co-localizes with FAK at cell periphery in spreading cells [33].

Regulatory relationships of PTK2

• However, efficient EGF-stimulated cell migration also requires FAK to be targeted, by its carboxy-terminal domain, to sites of integrin-receptor clustering [15].
• Our data suggest that a general function of PTEN is to down-regulate FAK and Shc phosphorylation, Ras activity, downstream MAP kinase activation, and associated focal contact formation and cell spreading [28].
• Melanoma chondroitin sulfate proteoglycan enhances FAK and ERK activation by distinct mechanisms [34].
• Taken together, our results suggest that CIB regulates platelet spreading through the regulation of FAK activation [19].
• Then, activated Pyk2 triggers the phosphorylation of FAK on Tyr407, promoting cell migration [22].
• Y397F and Y925F FAK point mutants inhibited TGFbeta-induced Elk-Gal activity, but only the Y397F mutant inhibited TGFbeta-stimulated collagen-promoter activity [35].

Other interactions of PTK2

• Expression of MCSP enhances integrin-mediated cell spreading, FAK phosphorylation, and activation of ERK1/2 [34].
• RAFTK, the second member of the focal adhesion kinase (FAK) family, is known to be activated in response to calcium flux in neuronal cells and integrin stimulation in megakaryocytes and B cells [36].
• Immunoprecipitation analysis indicates that CIB associates with focal adhesion kinase (FAK), a key regulator in focal complex formation, and up-regulates its activity [19].
• We propose that GIT1 and FAK cooperate to promote motility both by directly regulating focal complex dynamics and by the activation of Rac [37].
• First, disruption of the paxillin-binding site in the alpha(4) tail resulted in much less alpha(4)beta(1)-mediated phosphorylation of Pyk2 and FAK [38].

Analytical, diagnostic and therapeutic context of PTK2

• METHODS: Interaction between FAK and PLC gamma was determined by immunoprecipitation and immunoblotting [16].
• In immunofluorescence studies, reduction in PRL-1 seemed to decrease cell membrane protrusions with a reduction in actin fiber extensions in spite of continuous phosphorylation of Tyr397 FAK, which could reflect reduced adhesion turnover [39].
• We now suggest a mechanism by which FAK activates the signal transducer and activator of transcription (STAT) pathway, regulating cell adhesion and migration [40].
• Furthermore, FAK and paxillin phosphorylation was markedly blocked after treatment of HUVEC with AG1478, a selective inhibitor of epidermal growth factor receptor (EGFR) phosphorylation [41].
• Western blots measured cytoplasmic phosphorylated or total FAK and PKB [42].

References