Disease relevance of Ptk2

• FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth [1].
• Together, these results support a novel model for invasion that implicates FAK phosphorylation as important for delivery of viral capsids to the nuclear pore [2].
• Focal adhesion kinase plays a pivotal role in herpes simplex virus entry [2].
• Here we examine whether FAK downstream signaling pathways are affected in these cystic kidneys [3].
• We previously demonstrated that phosphorylation of FAK and paxillin is not downregulated in cystic kidneys from B cell lymphoma/leukemia-2 (bcl-2) -/- mice [3].

High impact information on Ptk2

• Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration [4].
• In nonneuronal cells, the tyrosine kinase FAK is a major regulator of cell motility through focal adhesions [4].
• Overexpression of the nonphosphorylatable mutant FAK S732A results in disorganization of the microtubule fork and impairment of nuclear movement in vitro, and neuronal positioning defects in vivo [4].
• We show here that integrin alpha8beta1, its ligand fibronectin and the integrin-regulated focal adhesion kinase (FAK) co-localize to the apical hair-cell surface where stereocilia are forming [5].
• Focal adhesion kinase (p125FAK): a point of convergence in the action of neuropeptides, integrins, and oncogenes [6].

Chemical compound and disease context of Ptk2

• The inhibition of RhoA by the C3 toxin (Clostridium botulinum toxin) restored endothelial barrier function in the FRNK-expressing cells [7].
• Additionally, treatment of cells with Clostridium difficile toxin B potently inhibited hyperosmotic stress-induced FAK tyrosine phosphorylation [8].
• Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK [9].
• We tested the hypothesis that FAK is a determinant of gemcitabine chemoresistance in pancreatic adenocarcinoma cells and examined the effect of inhibiting FAK expression on gemcitabine-induced cytotoxicity in vitro and in vivo [10].
• These results demonstrate that combination treatment with EGCG and dacarbazine strongly inhibits melanoma growth and metastasis, and the action mechanisms of EGCG are associated with the inhibition of cell spreading, cell-extracellular matrix and cell-cell interactions, MMP-9 and FAK activities [11].

Biological context of Ptk2

• Increased FAK tyrosine phosphorylation occurs upon integrin engagement with fibronectin [12].
• Focal adhesion kinase (FAK) is an important mediator of integrin signaling in the regulation of cell adhesion, migration, survival, and proliferation [13].
• Together, our data provide further insights into molecular mechanism for FAK to regulate cell cycle progression [13].
• Transcription activation of cyclin D1 by FAK requires both Ets family and KLF8 factors in a temporally differential manner [13].
• Using a series of deletion mutants and chimeric fusion proteins of PYK2/FAK, we determined that the NH2-terminal domain and tyrosine kinase activity of PYK2 were required for the efficient induction of apoptosis [14].

Anatomical context of Ptk2

• Here we show that cell-specific ablation of the murine gene Ptk2 (more commonly known as fak), encoding focal adhesion kinase (FAK), increases the number of axonal terminals and synapses formed by neurons in vivo [15].
• Our results show that fibronectin binding to integrins on NIH3T3 fibroblasts promotes c-Src and FAK association and formation of an integrin-activated signalling complex [12].
• FAK activity can influence the formation of distinct actin cytoskeletal structures such as lamellipodia and stress fibers in part through effects on small Rho GTPases, although the molecular interconnections of these events are not well defined [16].
• The FAK-deficient mast cells had a reduction in the content of chondroitin/dermatan sulfate, the major glycosaminoglycan component of the granular matrix [17].
• The FAK-deficient cells had fewer microvilli that were fused with each other, giving the cell surface a ruffled appearance [17].

Associations of Ptk2 with chemical compounds

• Mutation of tyrosine residue 925 of FAK (YENV motif) to phenylalanine blocks GRB2 SH2-domain binding to FAK in vitro [12].
• Focal adhesion kinase (FAK), a 125-kD protein tyrosine kinase activated by integrin engagement, appears to be involved in mediating cell attachment and survival [14].
• These SH3 domains bind to the same proline-rich region of FAK (APPKPSR) encompassing residues 711-717 [18].
• However, signal transduction from the high affinity IgE receptor for the secretion of histamine was similar in the wild-type, heterozygote, and the FAK-deficient cells [17].
• To elucidate the role of focal adhesion kinase (pp125FAK) in transformation, its phosphorylation in transformed fibroblasts was compared with that of detransformed fibroblasts induced by a histone deacetylase inhibitor, trichostatin A (TSA) [19].

Physical interactions of Ptk2

• In all cases, phosphorylation of the putative Grb2-binding site in Fak (Tyr-925) was almost undetectable [20].
• It resulted from decreased activity of Src family tyrosine kinase and/or decreased amount of Src kinase interacting with pp125FAK [19].
• This correlated with increased coprecipitation of SSeCKS with biotin-phalloidin-bound F-actin from FAK-/- compared to FAK+/+ cell lysates [21].
• Also, TNF-induced association of FAK with RIP and subsequent association of RIP with TRAF2 were not observed, resulting in a failure of RIP to recruit the IKK complex in FAK-/- cells [22].
• First, a beta1 integrin subunit deletion mutant affecting the putative FAK binding site supports activation of MAP kinase in adhering fibroblasts but not tyrosine phosphorylation of FAK [23].

Enzymatic interactions of Ptk2

• Src and FAK kinases cooperate to phosphorylate paxillin kinase linker, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness [24].
• It was found that FCS and fibronectin stimulated phosphorylating activity of FAK in the cells at the logarithmic phase of growth, but were inefficient in the confluent cells [25].
• Recently, we found that Cdk5 phosphorylates focal adhesion kinase (FAK) at Serine 732 in vitro and is responsible for this phosphorylation in the developing brain [26].
• Our data show that Src kinase activity is required for adhesion turnover associated with cell migration in cancer cells and that, in addition to the catalytic activity, Src also acts as an adaptor to recruit other kinases that can phosphorylate key substrates including FAK [27].
• Overexpression of N17 Rac only slightly altered the hyperosmotic stress-mediated localization of phosphorylated FAK to focal contacts [8].

Regulatory relationships of Ptk2

• Induced focal adhesion kinase (FAK) expression in FAK-null cells enhances cell spreading and migration requiring both auto- and activation loop phosphorylation sites and inhibits adhesion-dependent tyrosine phosphorylation of Pyk2 [28].
• The latter was induced by ERK2 phosphorylation under the control of FAK and PYK2 phosphorylation orchestrated in a time-dependent manner [29].
• Taken together, these findings indicate that MEKK1 interacts with FAK in focal adhesions and regulates IRS-1 expression [30].
• However, FRNK did not affect v-Src-stimulated Akt activation, cell growth in soft agar, or subcutaneous tumor formation in nude mice [1].
• TGF-beta receptor down-regulation was abrogated by treatments that inactivate FAK, whereas the expression of CL100 had no effect [31].

Other interactions of Ptk2

• This increase is shown to result from vinculin's modulation of paxillin-FAK interactions [32].
• In this study, we show that over-expression of PYK2, but not FAK, in rat and mouse fibroblasts leads to apoptotic cell death [14].
• Primary murine embryonic fibroblasts (MEFs) derived from mutant homozygotes display defective cell cycle coupled to impaired activation of the FAK-PI3K-Akt and Rac-JNK signaling pathways [33].
• Tyr-576 and Tyr-577 lie in the putative activation loop of the kinase domain, and FAK catalytic activity may be elevated through phosphorylation of these residues by associated Src family kinase [28].
• These defects were associated with deficiencies of PAK1, GSK3beta, myosin light chain, and FAK phosphorylation [34].

Analytical, diagnostic and therapeutic context of Ptk2

• Here, we report that FAK interacts with p190RhoGEF, a RhoA-specific GDP/GTP exchange factor, in neuronal cells and in brain tissue extracts by co-immunoprecipitation and co-localization analyses [16].
• Focal adhesion kinase activated by beta(4) integrin ligation to mCLCA1 mediates early metastatic growth [35].
• Compared with the controls, the mast cells that lack FAK were less metachromatic and by electron microscopy had granules that appeared largely electron lucid, although their histamine content was unchanged [17].
• Using a two-hybrid assay and deletion mutagenesis, the binding site of the FAK C-terminal focal adhesion targeting (FAT) domain was identified within the C-terminal coiled-coil domain of p190RhoGEF [16].
• Using affinity chromatography and yeast two-hybrid interaction screens, we identified ASAP1 as a major binding partner of protein tyrosine kinase focal adhesion kinase (FAK) [36].

References