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Front Biosci. Author manuscript; available in PMC 2011 July 14.
Published in final edited form as:
PMCID: PMC3136041

Focal Adhesion Kinase and p53 signal transduction pathways in cancer


Human cancer is characterized by a process of tumor cell motility, invasion, and metastasis. One of the critical tyrosine kinases that is linked to these processes of tumor invasion and survival is the Focal Adhesion Kinase (FAK). Our laboratory was the first to isolate FAK from human tumors, and we had demonstrated that FAK mRNA was upregulated in invasive and metastatic human breast and colon cancer samples. We have cloned FAK promoter and have found that FAK promoter contains p53 binding sites, and that p53 inhibits FAK transcription and regulates its expression in tumor samples. In addition, we have found a high correlation between FAK overexpression and p53 mutations in 600 population-based series of breast cancer patients. found that N-myc binds FAK promoter and induces FAK transcription in neuroblastoma cells. Thus, this review will be focused on FAK and p53 signal transduction pathways in cancer.

Keywords: Focal Adhesion Kinase, p53, cancer, Protein Interaction, Inhibitors, Tumorigenesis, Small Molecules, MDM-2, Survival, Apoptosis, Review


Focal Adhesion Kinase was discovered more than 17 years ago, as a protein that plays a critical role in intracellular processes of cell spreading, adhesion, motility, survival and cell cycle progression. One of the critical tyrosine kinases that are linked to the processes of tumor invasion and survival is the Focal Adhesion Kinase (FAK). The FAK gene encodes a non receptor tyrosine kinase that localizes at contact points of cells with extracellular matrix, and is activated by integrin (cell surface receptor) signaling. The FAK gene was first isolated from chicken embryo fibroblasts transformed by v-src (1). Our laboratory was the first to isolate FAK gene from human tumors, and we demonstrated that FAK mRNA was up-regulated in invasive and metastatic human breast and colon cancer samples (2). At the same time, matched samples of normal colon and breast tissue from the same patients had almost no detectable FAK expression. This was the first evidence that FAK can be regulated at the level of gene transcription, as well as other mechanisms (such as gene amplification). Subsequently, we have demonstrated up-regulation of FAK at the protein level in numerous types of human tumors, including colon, breast, thyroid, ovarian, melanoma, and sarcoma (3),(46), (7, 8) (Figure 1). In addition, we have found novel interaction of FAK with several binding partners, such as: RIP (9), linking FAK with the death-receptor pathways and p53 (10), linking FAK with the apoptotic/survival nuclear pathways (11), (12). In addition, we have cloned the regulatory promoter region of the FAK gene, and found its transcriptional up-regulation in cancer cell lines (13). We have found that FAK promoter contains p53 binding sites, and that p53 inhibits FAK transcription both in vitro (13) and in vivo (14). Thus, this review will be focused on FAK intracellular signaling in cancer, linking signaling from extracellular matrix to the nucleus. We will discuss the role Focal Adhesion Kinase (FAK) expression, localization, activity, protein-protein interaction, and survival signaling in the development of cancer. We will discuss the FAK structure, function, and the novel FAK-p53 cross-talk pathways in the junction of death and growth factor receptors and apoptotic and survival pathways. Then we will pay attention to novel therapeutics approaches to target these interaction and pathways in cancer.

Figure 1
Focal Adhesion Kinase is overexpressed in tumor samples. Immunohistochemical staining is shown for colon cancer sample. Left panel: normal tissue, right panel: matched tumor tissue from the same patient.


First, FAK cDNA encoding 125 kDa protein was isolated from chicken embryo cells (1). The human FAK (also known as PTK2, protein tyrosine kinase 2) gene has been mapped to chromosome 8 (15, 16). Human complete FAK mRNA sequence is a 3791 bases long sequence (17). We were the first group to isolate human FAK cDNA from the primary sarcoma tissue and found increased FAKmRNA in tumor samples compared with normal tissue samples (2).

Recently, the genomic structure of FAK has been characterized (18). The gene coding sequence contains 34 exons, and genomic sequence spans 230 kb (18). We were the first group to clone and characterize the human FAK promoter, regulating FAK expression (13). The core promoter contains 600 base pairs and includes many transcription binding sites, such as AP-1, AP-2, SP-1, PU.1, GCF, TCF-1, EGR-1, NF-kappa B and p53(13). Interestingly, we found two transcription binding sites for p53 in the FAK promoter, and found that p53 can block FAK promoter activity (13). Recently, mouse promoter has been cloned and it is highly homologous to the human promoter, and contained the same binding sites (18).


The FAK protein is a 125 kDa tyrosine kinase (p125FAK) with a large amino-N-terminal domain, exhibiting homology with a FERM (protein 4.1, ezrin, radixin and moesin) domain with an autophosphorylation site (Y-397), a central catalytic domain, and a large carboxy-C-terminal domain that contains a number of potential protein interacting sites, including two proline-rich domains and FAT domain (1921) (Figure 2).

Figure 2
Focal Adhesion Kinase (FAK) structure. FAK has the N-terminal, Kinase domain and the C-terminal domains. The N-terminal domain has Y-397-Y-autophosphorylation site. The Kinase domain has Y576/577 tyrosines important for catalytic activity of FAK. The ...

4.1. FAK N-terminal domain

The function of the N-terminal, homologous to FERM domain was linked to the binding of integrins, via their β subunits(22). The N-terminal domain (1–415 a.a) of FAK protein contains the major autophosphorylation site Y397-tyrosine, that in phosphorylated form becomes a binding site of SH-2 domain of Src, leading to its conformational changes and activation (19). The crystal structure of the N-terminal domain of avian FAK, containing FERM domain has been recently described (23). Interesting negative regulation of FAK function by FERM domain was revealed by (24) and (25). Tyrosine phosphorylation of FAK causes binding and activation of Src that leads to tyrosine phosphorylation Y407 and Y576, Y577 - major phosphorylation sites in the catalytic domain of FAK; Y861 and Y925 (19, 26), and then to phosphorylation of FAK binding proteins, such as paxillin and Cas (27). This cascade causes subsequent cytoskeletal changes and activation of RAS-MAPK (mitogen-activated protein kinase) signaling pathways (26, 28). Thus, FAK-Src signaling complex activates many other signaling proteins, involved in survival, motility and metastatic, invasive phenotype in cancer cells. Phosphorylated Y397 FAK is able to recruit another important signaling protein, p85 PI3-kinase (phosphoinositide 3-kinase), growth factor receptor bound protein Grb 7, phospholipase Cgamma(PLCgamma) and others. Thus, the N-terminal domain of FAK binds to the extracellular matrix receptors, integrins, growth factor receptors or important signaling cytoplasmic, cytoskeletal and nuclear proteins, mediating signaling from the extracellular matrix to the cytoplasm and nucleus and controlling cytoskeletal changes, survival, motility and invasion.

4.2. FAK Kinase domain

The central kinase (catalytic) domain of FAK (416–676 amino-acids) is the most conserved domain in vertebrate and non-vertebrate organisms (18). The central catalytic domain of FAK contains Y576 and Y577, major phosphorylation sites, and also K454, ATP binding site (Figure 2). Phosphorylation of FAK by Src on Y576 and Y577 is an important step in the formation of active signaling complex and is required for maximal enzymatic activity of FAK (29). The crystal structure of FAK kinase domain revealed open conformation similar to the fibroblast growth factor receptor-1 (FGFR-1) and vascular endothelial growth factor receptor (VEGFR) (30). The FAK kinase domain structure has an unusual has been recently solved (25).

4.3. FAK C-terminal domain

Different proteins can bind to the C-terminal domain of p125FAK (677–1052 amino-acids), including paxillin, p130cas, PI3-kinase, GTP-ase-activating protein Graf, leading to changes in the cytoskeleton and to activation of the Ras-MAP kinase pathway (21, 28, 31, 32). The carboxyterminal domain of FAK contains sequences responsible for its targeting to focal adhesions, also known as the FAT domain. Alternative splicing of FAK results in autonomous expression of the C-terminal part of FAK, FAK-related non-kinase (FRNK) (33). The crystal structure of the C-terminal domain of FAK, FAT, has been determined recently by several groups (34),(35) that can exist as dimer or monomer, allowing binding of several binding partners. FAT domain mediates signaling through Grb-2 binding to Y925 site of FAK (36).


FAK has numerous functions in cell survival, motility, metastasis, invasion and angiogenesis.

5.1. Survival function

FAK plays a major role in the survival signaling and has been linked to detachment-induced apoptosis or anoikis (37). It has been shown that constitutively activated forms of FAK rescued epithelial cells from anoikis, suggesting that FAK can regulate this process (32, 3740). Similarly, both FAK antisense oligonucleotides (41, 42), as well as dominant-negative FAK protein (FAK-CD), caused cell detachment and apoptosis in tumor cells (41, 4350). The anti-apoptotic role of FAK was also demonstrated in FAK-transfected FAK/HL60 cells that were highly resistant to apoptosis induced with etoposide and hydrogen peroxide compared with the parental HL-60 cells or the vector-transfected cells (51, 52). HL-60/FAK cells activated the AKT pathway and NF-kappa B survival pathways with the induction of inhibitor-of-apoptosis proteins, IAPs (51). We have demonstrated that EGFR and Src signaling cooperate with FAK survival signaling in colon and breast cancer cells (45),(46, 50, 53). We have also demonstrated that simultaneous inhibition of Src and FAK or EGFR and FAK pathways was able to increase apoptosis in cancer cells (45); (46). Thus, cancer cells use cooperative function of kinases and growth factor receptor signaling to increase survival.

5.2. Motility function

FAK has also been shown to be important for cell motility (28, 5456). FAK-null embryos exhibit decreased motility in vitro (57). Furthermore, enforced expression of FAK stimulated cell migration (58, 59). Cell migration is initiated by protrusion at the leading edge of the cell, by the formation of peripheral adhesions, exertion of force on these adhesions, and then the release of the adhesions at the rear of the cell (60). Focal adhesion kinase (FAK) is involved in the regulation of migration, although the precise mechanism of this FAK-regulated migration is unclear. FAK has been shown to be required for the organization of the leading edge in migrating cells by coordinating integrin signaling in order to direct the correct activation of membrane protrusion (60). SH2 domain of Src, targeting Src to focal adhesions and Y397 activity has been shown to be important for motility (61). PI3 kinase has been also shown to be critical for FAK-mediated motility in Chinese hamster ovary (CHO) cells (62). Tumor suppressor gene PTEN, encoding phosphatase has been shown to interact with FAK, caused its dephosphorylation and blocked motility (63). Moreover, Y397FAK was important for PTEN interaction with FAK (64). Overexpression of FAK reversed the inhibitory effect of PTEN on cell migration (63).

5.3. Metastasis, invasion and angiogenesis functions

Activation of FAK is linked to invasion and metastasis signaling pathways. FAK was important in Erb-2/Erb3-induced oncogenic transformation and invasion (65). Inhibition of FAK in FAK-proficient invasive cancer cells prevented cell invasion and metastasis processes (65). In addition, FAK has been shown to be activated in invading fibrosarcoma and regulated metastasis (66). Inhibition of FAK with dominant-negative FAK-CD disrupted invasion of cancer cells (56). We have also shown that high FAK expression in breast cancers associated with tumor aggressive phenotype (67). Subsequently, we analysed FAK expression in pre-invasive ductal carcinoma in situ, DCIS tumors and detected protein overexpression in preivasive tumors (8), suggesting that FAK survival function occurs as an early event in breast tumorigenesis.

Overexpression of focal adhesion kinase in vascular endothelial cells promoted angiogenesis in transgenic mice (68). Overexpession of FAK induced human retinal endothelial cell (HREC) migration and in vivo angiogenesis (69). FAK activity and phosphorylation of Y925 site of FAK promoted angiogenic switch during tumor progression (70). FAK-Grb2-MAPK signaling has been shown to be important for promoting angiogenesis. Furthermore, inhibition of FAK resulted in disruption of angiogenesis (70). FAK and Src catalytic activities are important to promote VEGF-dependent angiogenesis (71). Thus, FAK is involved in angiogenesis and plays a major role in tumorigenesis.


FAK has numerous binding partners in the N-terminal, Central and C-terminal domains. The N-terminal domain of FAK contains one proline-rich domain, and the C-terminal domain of FAK contains another two proline-rich domains that are sites of binding proteins, containing SH3 domains. The C-terminal part of C-terminal domain of FAK (853–1012 a.a) called FAT (Focal adhesion targeting domain) domain that is necessary for targeting of FAK to focal adhesion complexes through binding with different proteins (paxillin, talin, Rho, etc).

The first indirect link of FAK and p53 was provided by (72). The authors showed that extracellular matrix survival signals mediated by FAK suppressed p53-directed apoptosis (72). We were the first to find direct binding of FAK and p53 proteins in different cancer cells (10). The N-terminal domain of p53 (1–92 a.a.) interacts with the N-terminal domain of FAK (10). We have shown previously that p53 can bind FAK promoter and inhibit its luciferase activity (10). Moreover, FAK can block p53 transcriptional activity of p21, BAX and Mdm-2. Thus, there is a feedback loop mechanism of regulation of these two proteins (12). The recent report confirmed direct binding of the N-terminal domain of FAK with p53 and also found interaction of FAK and Mdm-2 providing a novel mechanism of FAK-Mmd-2-mediated ubiquitination of p53 in the nucleus (73). These data link FAK with the p53 tumor suppressor signaling that we will discuss below.

6.1. Structure and function of p53 Protein

p53 is a tumor suppressor gene, which is located at chromosome 17p13 region, spans 20 kb and contains 11 exons (74). The p53 protein is a phosphoprotein transcription factor that binds to 5′Pu-Pu-Pu-C-A/T-T/AG-Py-Py-Py3′ (Pu-purine; Py-pyrimidine) consensus DNA sequence in the promoters of the genes and activates their transcription (75). The p53 gene encodes 393 amino-acid protein. The promoter of p53 lacks TATA box and contains various binding sites for known transcription factors, such as NF-kappa B, Sp1 or c-Jun (76).

p53 protein contains three domains: an acidic N-terminal, transcriptional activating domain (1–92 aa.), Central, DNA-binding domain (102–292 amino-acids) and C-terminal (102–292 amino-acids), tetramerization domain (325–393 amino-acids). The p53 protein contains many sites for phosphorylation by different kinases: ATM, Chk2, ATR, JNK, MAPK, CKI, CKII).

6.2. Mutations of p53 in cancer

It is known that the p53 tumor suppressor is the most frequent target for genetic alterations in human cancers and is mutated in almost 50% of all tumors (7781). Inactivation of p53 gene is a critical step in tumorigenesis (82). Following induction by variety of cell stresses such as DNA damage, hypoxia, presence of activated oncogenes, p53 up-regulates a set of genes that can promote cell death and growth arrest, such as p21, GADD45, cyclin G, Bax, reviewed in (83). Recently, it was shown that p53 can repress promoter activities of a number of anti-apoptotic genes and cell-cycle genes (survivin (84), cyclin B1, cdc2, (85, 86), cdc25 c (87), stathmin (88), Map4(89), bcl-2 (85).

Among reported mutations, 75% are missense mutations, with 80% of them located in the DNA-binding domain of p53 (76), and 30% of the mutations are in 5 hot-spot codons: 175, 245, 248, 273 and 282). Arginine residues (248 and 273) involved in interaction of p53 with DNA, and arginines (175 and 282) stabilize DNA-binding sequence (76). Wild type p53 binds to promoters differently, for example, p53 activates p21 promoter with higher affinity than Bax promoter (76). Some p53 mutants are able to transactivate different genes, such as EGFR, MDR1, c-Myc, PCNA, IGF-2 or VEGF, providing growth-promoting phenotypes and drug-resistance (76).

6.3. p53 binds and represses FAK promoter

Our group was first to clone human FAK promoter and to find two p53 binding sites in the FAK promoter (13). We have shown that p53 can bind FAK promoter and inhibit its transcriptional activity in vitro by EMSA (13) and in vivo by ChIP (chromatin immunoprecipitation) assay (14) (Figure 3). In addition, several other transcription factors, such as SP-1, AP-2, TCF-1 and NF-kappa B were shown to be present in the FAK promoter. NF-kappa B protein has been shown to be linked to p53 pathway (90). For example, activation of Cox-2 transcription required co-operation of NF-kappa B and p53 (90). Thus, regulation of FAK promoter can also include association of these two transcription factors, thus providing additional indirect p53-regulated FAK expression mechanism.

Figure 3
Immunohistochemical staining of FAK and p53 in colon tumor. FAK is stained with FITC, p53 is stained with Rhodamin and nuclei with Hoechst. Arrow indicate co-localization of FAK and p53 (yellow color).

Moreover, while wild type inhibited FAK promoter activity, mutant p53 did not inhibit FAK promoter activity, as wild type did. The recent global analysis of p53 transcription factor binding sites demonstrated that induction of HCT116 colon cancer cells with 5-fluorouracil transcriptionally down-regulated FAK (91). Thus, the authors suggested that p53 can suppress metastasis through down-regulation of metastasis-related genes, as FAK. We have shown recently that p53 can regulate FAK expression in human cancer cells (14). FAK mRNA and protein was increased in primary colon and breast tumors with mutant p53 versus wild type p53 tumors (14). In addition population-based study of 600 breast cancer tumors demonstrated high correlation between FAK overexpression and p53 mutation (12,14).

6.4. Direct FAK and p53 protein binding

We have demonstrated that the N-terminal transactivation domain of (1–92 a.a.) of p53 physically directly binds the N-terminal domain of FAK (10). There have been several reports on the localization of the N-terminal part of FAK in the nucleus (92), (47), (93), (92, 94). Furthermore, the N-terminus of FAK was shown to cause apoptosis in breast cancer cell lines (47) and its nuclear localization was regulated by caspase inhibitors in endothelial cells (94). In addition, p53 has been reported to be localized in the cytoplasm (95). P53 directly activated Bax and released pro-apoptotic molecules, activating multidomain proteins in the cytoplasm. This mechanism required 62–91 residues in the proline-rich N-terminal domain of p53 (95). We detected interaction and co-localization of p53 and FAK in tumor colon cancer samples (Figure 3, marked by arrows). Consistent with these findings, recently we have shown that 7 amino-acids (65–71 a.a.) from the proline-rich region of p53 were involved in interaction with FAK (96).

6.5. Direct FAK and Mdm-2 protein binding

The recent report demonstrated that FAK binds also Mdm-2 and causes p53 proteosomal degradation in the nucleus (73) (Figure 4). Thus, understanding the detail mechanism and functions of FAK/p53-interaction may ultimately have important implications for targeted cancer therapy.

Figure 4
Sequestration and Integration Model of FAK functions in cells and signal transduction pathways from extracellular matrix to the cytoplasm and nucleus. The central part of the scheme is modified from (12). Focal Adhesion Kinase integrates signals from ...

6.6. Feedback model of FAK-p53 protein interaction

We have shown that p53 can suppress FAK transcription.(13, 14). Recently, global characterization of 65,572 p53 ChIP DNA fragments was done in HCT116 colorectal cancer cell line, treated with 5-fluorouracil for 6 hours that activated p53 (91). The authors identified novel targets of p53, that are involved in cell adhesion, migration and metastasis, and PTK2 or FAK was one of these kinases (91). Interestingly, in HCT116 cells, treated with 5-fluorouracil that increases p53 level, PTK2 (FAK) expression was also inhibited (91).

We have also shown that FAK can suppress transcriptional activity of p53 through its interaction, as p53-mediated activation of p53-targets: p21, Mdm-2 and Bax was blocked by overexpression of FAK (10). (Figure 4). Thus, p53 can regulate FAK (by inhibiting transcription, and in turn, FAK can regulate p53 by sequestering it from apoptotic signaling and then ubiquitination that decreases p53 transcriptional functions (73). Thus FAK and p53 can be regulated through a comprising a feedback mechanism (12) (Figure 4). Mutations of p53 that are frequently found in cancers, can lead to up-regulation and overexpression of FAK. Thus, novel mechanisms of FAK survival function, FAK and wild type or mutant p53 interactions remain to be discovered during carcinogenesis.


Recently, Focal Adhesion Kinase has been proposed to be a new therapeutic target (26). Several in vitro approaches used to down-regulate FAK-adenoviral FAK-CD (dominant-negative FAK) (44), anti-sense oligonucleotides (42) and siRNA for FAK (97). The melanoma cells treated with antisense oligonucleotides lost their attachment and underwent apoptosis (41) (42). The same effect was observed with Ad-FAK-CD in different cancer cells. While breast cancer cells underwent apoptosis by down-regulation of FAK with FAK-CD, normal MCF-10A and HMEM cells did not undergo apoptosis (44). These inhibitors applications are limited due to the cell toxicity in vivo. Thus, developing small-molecule drugs is critical for future FAK-targeting therapy, involving kinase inhibitors and drugs, targeting FAK-protein interactions.

There were no pharmacological inhibitors, reducing FAK kinase activity. Recently Novartis Inc. developed novel FAK inhibitors down-regulation its kinase activity (98). The novel Novartis FAK inhibitor, TAE-226 recently was employed in brain cancer and effectively inhibited FAK signaling and caused apoptosis in these cells (99). We also used TAE-226 inhibitor in breast (100), neuroblastoma (101) and pancreatic cancer cells (102) and found that this inhibitor can effectively cause apoptosis in these different types of cancer. Although, it can inhibit also other signaling pathways in addition to FAK, such as IGFR-1. Another, ATP-targeting site inhibitor of FAK, Pfizer-PF-573,228 has been recently described (103). Another Pfizer inhibitor PF-562,271 with high specificity in inhibiting FAK activity has been shown to be effective in tumor xenograft models in vivo (104) and on bone tumors(105). The future detail studies will be needed to address specificity of these drugs.


One of the approaches to inhibit FAK function can be targeting its protein-protein interaction with its binding partners, such p53. Small-molecule drugs can be found either through high-throughput screening or through database searches using protein crystal structures.

Small molecule drug inhibitors are effectively used to target p53 protein-protein interactions, particularly with Mdm-2 protein (106). The first potent inhibitors targeting p53-Mdm-2 interaction have been identified by high-throughput screening followed by structure-based optimization (106). The screening identified nutlins that represent a class of cis-imidazole analogues that bind to the p53 pocket interacting with Mdm-2. The same strategy can be used to target interaction with FAK and p53, FAK and Mdm-2 and combination therapy approaches can be applied.

Recently we used the crystal structure of the N-terminus of FAK, and screened 200,000 small molecules from the NCI bank for their ability to target this binding site and for their oral bioavailability using Lipinski rules. We identified several potential lead compounds and tested them on human breast, colon, and melanoma cell lines for their ability to disrupt p53-FAK or VEGFR-3-FAK binding and to induce cancer cell death. We found several potential compounds that were able to decrease FAK phosphorylation, decrease cell viability and activate PARP, suggesting its potential role in future therapy.


Thus, understanding of FAK biology during tumorigenesis, mechanisms of its up-regulation in different tumors, role in stem cell biology, angiogenesis, motility, and especially mechanisms of its direct physical interaction with protein binding partners and their down-stream signaling pathways will be critical in developing targeted therapeutics.

Studies with peptide inhibitors already have indicated that blockade of specific protein–protein interactions has therapeutic promise for treating a variety of diseases, including cancer (107112). Small molecule drugs are particularly attractive as inhibitors of intracellular protein–protein interactions due to the ability to modify their structures to achieve optimal target binding. Recently, the N-terminal domain of Pyk-2 (protein highly homologous to FAK) has been shown to interact with p53 (113). Although, we did not find direct interaction of the full length Pyk-2 protein and p53 in pull-down assay (10), the mechanism of this N-terminal domain and p53 interaction is intriguing. Thus, targeting of FAK-53 signaling pathways can be important in cancer treatment programs. The computer modeling approach that we developed recently, targeting FAK autophosphorylation site showed that this inhibitor can decrease breast and pancreatic tumorigenesis (114, 115). Thus, as we further define the mechanisms of FAK and p53 signaling in cancer cells, we will identify the optimal sites for targeting these protein and disrupting its signaling to cause apoptosis in human tumors. The correlation of p53 mutation and FAK overexpression in 600 breast tumors (116) can be a basis for future therapies in tumors with mutant p53 and overexpressed FAK.


The work was supported by a Susan Komen for the Cure grant to (VMG) and by an NCI RO1 grant (WGC).


Focal Adhesion Kinase
murine double minute 2


1. Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons JT. pp125fak a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proceedings of the National Academy of Sciences of the United States of America. 1992;89(11):5192–5196. [PubMed]
2. Weiner TM, Liu ET, Craven RJ, Cance WG. Expression of focal adhesion kinase gene and invasive cancer. Lancet. 1993;342(8878):1024–1025. [PubMed]
3. Owens LV, Xu L, Craven RJ, Dent GA, Weiner TM, Kornberg L, Liu ET, Cance WG. Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Research. 1995;55(13):2752–2755. [PubMed]
4. Owens LV, Xu L, Dent GA, Yang X, Sturge GC, Craven RJ, Cance WG. Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer. Annals of Surgical Oncology. 1996;3(1):100–105. [PubMed]
5. Cance WG, Harris JE, Iacocca MV, Roche E, Yang X, Chang J, Simkins S, Xu L. Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues. correlation with preinvasive and invasive phenotypes. Clin Cancer Res. 2000;6(6):2417–2423. [PubMed]
6. Judson PL, He X, Cance WG, Van Le L. Overexpression of focal adhesion kinase, a protein tyrosine kinase, in ovarian carcinoma. Cancer. 1999;86(8):1551–1556. [PubMed]
7. Lark AL, Livasy CA, Calvo B, Caskey L, Moore DT, Yang X, Cance WG. Overexpression of focal adhesion kinase in primary colorectal carcinomas and colorectal liver metastases. immunohistochemistry and real-time PCR analyses. Clin Cancer Res. 2003;9(1):215–222. [PubMed]
8. Lightfoot HM, Jr, Lark A, Livasy CA, Moore DT, Cowan D, Dressler L, Craven RJ, Cance WG. Upregulation of focal adhesion kinase (FAK) expression in ductal carcinoma in situ (DCIS) is an early event in breast tumorigenesis. Breast Cancer Res Treat. 2004;88(2):109–116. [PubMed]
9. Kurenova E, Xu L-H, Yang X, Baldwin AS, Jr, Craven RJ, Hanks SK, Liu Z-g, Cance WG. Focal Adhesion Kinase Suppresses Apoptosis by Binding to the Death Domain of Receptor-Interacting Protein. Mol Cell Biol. 2004;24(10):4361–4371. [PMC free article] [PubMed]
10. Golubovskaya VM, Finch R, Cance WG. Direct interaction of the N-terminal domain of focal adhesion kinase with the N-terminal transactivation domain of p53. J Biol Chem. 2005;280(26):25008–25021. [PubMed]
11. Golubovskaya VM, Cance WG. Focal adhesion kinase and p53 signaling in cancer cells. Int Rev Cytol. 2007;263:103–153. [PubMed]
12. Cance WG, Golubovskaya VM. Focal Adhesion Kinase Versus p53. Apoptosis or Survival? Sci Signal. 2008;1(20):pe22. [PMC free article] [PubMed]
13. Golubovskaya V, Kaur A, Cance W. Cloning and characterization of the promoter region of human focal adhesion kinase gene. nuclear factor kappa B and p53 binding sites*1. Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 2004;1678(2–3):111–125. [PubMed]
14. Golubovskaya VM, Finch R, Kweh F, Massoll NA, Campbell-Thompson M, Wallace MR, Cance WG. p53 regulates FAK expression in human tumor cells. Mol Carcinog. 2008;47(5):373–382. [PMC free article] [PubMed]
15. Fiedorek FT, Jr, Kay ES. Mapping of the focal adhesion kinase (Fadk) gene to mouse chromosome 15 and human chromosome 8. Mammalian Genome. 1995;6(2):123–126. [PubMed]
16. Agochiya M, Brunton VG, Owens DW, Parkinson EK, Paraskeva C, Keith WN, Frame MC. Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells. Oncogene. 1999;18(41):5646–5653. [PubMed]
17. Whitney GS, Chan PY, Blake J, Cosand WL, Neubauer MG, Aruffo A, Kanner SB. Human T and B lymphocytes express a structurally conserved focal adhesion kinase, pp125FAK. DNA & Cell Biology. 1993;12(9):823–830. [PubMed]
18. Corsi JM, Rouer E, Girault JA, Enslen H. Organization and post-transcriptional processing of focal adhesion kinase gene. BMC Genomics. 2006;7:198. [PMC free article] [PubMed]
19. Hanks SK, Polte TR. Signaling through focal adhesion kinase. Bioessays. 1997;19(2):137–145. [PubMed]
20. Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT. Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Molecular & Cellular Biology. 1994;14(3):1680–1688. [PMC free article] [PubMed]
21. Schaller MD, Parsons JT. Focal adhesion kinase and associated proteins. Current Opinion in Cell Biology. 1994;6(5):705–710. [PubMed]
22. Schaller MD, Otey CA, Hildebrand JD, Parsons JT. Focal adhesion kinase and paxillin bind to peptides mimicking beta integrin cytoplasmic domains. Journal of Cell Biology. 1995;130(5):1181–1187. [PMC free article] [PubMed]
23. Ceccarelli DF, Song HK, Poy F, Schaller MD, Eck MJ. Crystal structure of the FERM domain of focal adhesion kinase. J Biol Chem. 2006;281(1):252–9. [PubMed]
24. Cooper LA, Shen TL, Guan JL. Regulation of focal adhesion kinase by its amino-terminal domain through an autoinhibitory interaction. Mol Cell Biol. 2003;23(22):8030–8041. [PMC free article] [PubMed]
25. Lietha D, Cai X, Ceccarelli DF, Li Y, Schaller MD, Eck MJ. Structural basis for the autoinhibition of focal adhesion kinase. Cell. 2007;129(6):1177–87. [PMC free article] [PubMed]
26. McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC. The role of focal-adhesion kinase in cancer - a new therapeutic opportunity. Nat Rev Cancer. 2005;5(7):505–515. [PubMed]
27. Schaller MD, Hildebrand JD, Parsons JT. Complex formation with focal adhesion kinase. A mechanism to regulate activity and subcellular localization of Src kinases. Mol Biol Cell. 1999;10(10):3489–3505. [PMC free article] [PubMed]
28. Hanks SK, Ryzhova L, Shin NY, Brabek J. Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility. Front Biosci. 2003;8:d982–96. [PubMed]
29. Calalb MB, Polte TR, Hanks SK. Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity. a role for Src family kinases. Molecular & Cellular Biology. 1995;15(2):954–963. [PMC free article] [PubMed]
30. Nowakowski J, Cronin CN, McRee DE, Knuth MW, Nelson CG, Pavletich NP, Rogers J, Sang BC, Scheibe DN, Swanson RV, Thompson DA. Structures of the cancer-related Aurora-A, FAK, and EphA2 protein kinases from nanovolume crystallography. Structure. 2002;10(12):1659–1667. [PubMed]
31. Parsons JT. Focal adhesion kinase. the first ten years. J Cell Sci. 2003;116(Pt 8):1409–16. [PubMed]
32. Windham TC, Parikh NU, Siwak DR, Summy JM, McConkey DJ, Kraker AJ, Gallick GE. Src activation regulates anoikis in human colon tumor cell lines. Oncogene. 2002;21(51):7797–7807. [PubMed]
33. Richardson A, Parsons JT. Signal transduction through integrins. a central role for focal adhesion kinase? Bioessays. 1995;17(3):229–236. [PubMed]
34. Hayashi I, Vuori K, Liddington RC. The focal adhesion targeting (FAT) region of focal adhesion kinase is a four-helix bundle that binds paxillin. Nat Struct Biol. 2002;9(2):101–106. [PubMed]
35. Prutzman KC, Gao G, King ML, Iyer VV, Mueller GA, Schaller MD, Campbell SL. The focal adhesion targeting domain of focal adhesion kinase contains a hinge region that modulates tyrosine 926 phosphorylation. Structure (Camb) 2004;12(5):881–891. [PubMed]
36. Arold ST, Hoellerer MK, Noble ME. The structural basis of localization and signaling by the focal adhesion targeting domain. Structure. 2002;10(3):319–327. [PubMed]
37. Frisch SM, Vuori K, Ruoslahti E, Chan-Hui PY. Control of adhesion-dependent cell survival by focal adhesion kinase. Journal of Cell Biology. 1996;134(3):793–9. [PMC free article] [PubMed]
38. Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol. 2001;13(5):555–562. [PubMed]
39. Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol. 1997;9(5):701–6. [PubMed]
40. Frisch SM. Evidence for a function of death-receptor-related, death-domain-containing proteins in anoikis. Curr Biol. 1999;9(18):1047–1049. [PubMed]
41. Xu LH, Owens LV, Sturge GC, Yang X, Liu ET, Craven RJ, Cance WG. Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells. Cell Growth Differ. 1996;7(4):413–418. [PubMed]
42. Smith CS, Golubovskaya VM, Peck E, Xu LH, Monia BP, Yang X, Cance WG. Effect of focal adhesion kinase (FAK) downregulation with FAK antisense oligonucleotides and 5-fluorouracil on the viability of melanoma cell lines. Melanoma Res. 2005;15(5):357–362. [PubMed]
43. Xu LH, Yang X, Craven RJ, Cance WG. The COOH-terminal domain of the focal adhesion kinase induces loss of adhesion and cell death in human tumor cells. Cell Growth Differ. 1998;9(12):999–1005. [PubMed]
44. Xu L-h, Yang X-h, Bradham CA, Brenner DA, Baldwin AS, Craven RJ, Cance WG. The focal adhesion kinase suppresses transformation-associated, anchorage-Independent apoptosis in human breast cancer cells. J Biol Chem. 2000;275:30597–30604. [PubMed]
45. Golubovskaya V, Beviglia L, Xu LH, Earp HS, 3rd, Craven R, Cance W. Dual inhibition of focal adhesion kinase and epidermal growth factor receptor pathways cooperatively induces death receptor-mediated apoptosis in human breast cancer cells. J Biol Chem. 2002;277(41):38978–38987. [PubMed]
46. Golubovskaya VM, Gross S, Kaur AS, Wilson RI, Xu LH, Yang XH, Cance WG. Simultaneous inhibition of focal adhesion kinase and SRC enhances detachment and apoptosis in colon cancer cell lines. Mol Cancer Res. 2003;1(10):755–764. [PubMed]
47. Beviglia L, Golubovskaya V, Xu L, Yang X, Craven RJ, Cance WG. Focal adhesion kinase N-terminus in breast carcinoma cells induces rounding, detachment and apoptosis. Biochem J. 2003;373(Pt 1):201–210. [PubMed]
48. van De Water B, Houtepen F, Huigsloot M, Tijdens IB. Suppression of chemically induced apoptosis but not necrosis of renal proximal tubular epithelial (LLC-PK1) cells by focal adhesion kinase (FAK). Role of FAK in maintaining focal adhesion organization after acute renal cell injury. J Biol Chem. 2001;276(39):36183–36193. [PubMed]
49. Gabarra-Niecko V, Schaller MD, Dunty JM. FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev. 2003;22(4):359–74. [PubMed]
50. Park HB, Golubovskaya V, Xu L, Yang X, Lee JW, Scully S, 2nd, Craven RJ, Cance WG. Activated Src increases adhesion, survival and alpha2-integrin expression in human breast cancer cells. Biochem J. 2004;378(Pt 2):559–567. [PubMed]
51. Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, Kasahara T. Anti-apoptotic Role of Focal Adhesion Kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of fak in a human leukemic cell line, HL-60. J Biol Chem. 2000;275(21):16309–16315. [PubMed]
52. Kasahara T, Koguchi E, Funakoshi M, Aizu-Yokota E, Sonoda Y. Antiapoptotic action of focal adhesion kinase (FAK) against ionizing radiation. Antioxid Redox Signal. 2002;4(3):491–499. [PubMed]
53. Park HB, Xu L-H, Yang X, Cance WG. Activated c-Src rescues cell rounding and loss of adhesion caused by attenuation of the focal adhesion kinase in human breast cancer cells. Surg Forum. 1999;L:346–7.
54. Schlaepfer DD, Mitra SK. Multiple connections link FAK to cell motility and invasion. Curr Opin Genet Dev. 2004;14(1):92–101. [PubMed]
55. Schaller MD. Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim Biophys Acta. 2001;1540(1):1–21. [PubMed]
56. Hauck CR, Sieg DJ, Hsia DA, Loftus JC, Gaarde WA, Monia BP, Schlaepfer DD. Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res. 2001;61(19):7079–90. [PubMed]
57. Illc D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, Nomura S, Fujimoto J, Okada M, Yamamoto T, et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature. 1995;377(6549):539–544. [PubMed]
58. Sieg DJ, Hauck CR, Schlaepfer DD. Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J Cell Sci. 1999;112(Pt):2677–2691. [PubMed]
59. Hildebrand JD, Schaller MD, Parsons JT. Identification of sequences required for the efficient localization of the focal adhesion kinase, pp125FAK, to cellular focal adhesions. Journal of Cell Biology. 1993;123(4):993–1005. [PMC free article] [PubMed]
60. Tilghman RW, Slack-Davis JK, Sergina N, Martin KH, Iwanicki M, Hershey ED, Beggs HE, Reichardt LF, Parsons JT. Focal adhesion kinase is required for the spatial organization of the leading edge in migrating cells. J Cell Sci. 2005;118(Pt 12):2613–2623. [PubMed]
61. Yeo MG, Partridge MA, Ezratty EJ, Shen Q, Gundersen GG, Marcantonio EE. Src SH2 arginine 175 is required for cell motility. specific focal adhesion kinase targeting and focal adhesion assembly function. Mol Cell Biol. 2006;26(12):4399–4409. [PMC free article] [PubMed]
62. Reiske HR, Kao SC, Cary LA, Guan JL, Lai JF, Chen HC. Requirement of phosphatidylinositol 3-kinase in focal adhesion kinase-promoted cell migration. J Biol Chem. 1999;274(18):12361–12366. [PubMed]
63. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 1998;280(5369):1614–1617. [PubMed]
64. Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM. PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem. 1999;274(29):20693–703. [PubMed]
65. Benlimame N, He Q, Jie S, Xiao D, Xu YJ, Loignon M, Schlaepfer DD, Alaoui-Jamali MA. FAK signaling is critical for ErbB-2/ErbB-3 receptor cooperation for oncogenic transformation and invasion. J Cell Biol. 2005;171(3):505–516. [PMC free article] [PubMed]
66. Hanada M, Tanaka K, Matsumoto Y, Nakatani F, Sakimura R, Matsunobu T, Li X, Okada T, Nakamura T, Takasaki M, Iwamoto Y. Focal adhesion kinase is activated in invading fibrosarcoma cells and regulates metastasis. Clin Exp Metastasis. 2005;22(6):485–94. [PubMed]
67. Lark AL, Livasy CA, Dressler L, Moore DT, Millikan RC, Geradts J, Iacocca M, Cowan D, Little D, Craven RJ, Cance W. High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype. Mod Pathol. 2005;18(10):1289–94. [PubMed]
68. Peng X, Ueda H, Zhou H, Stokol T, Shen TL, Alcaraz A, Nagy T, Vassalli JD, Guan JL. Overexpression of focal adhesion kinase in vascular endothelial cells promotes angiogenesis in transgenic mice. Cardiovasc Res. 2004;64(3):421–430. [PubMed]
69. Kornberg LJ, Shaw LC, Spoerri PE, Caballero S, Grant MB. Focal adhesion kinase overexpression induces enhanced pathological retinal angiogenesis. Invest Ophthalmol Vis Sci. 2004;45(12):4463–4469. [PubMed]
70. Mitra SK, Mikolon D, Molina JE, Hsia DA, Hanson DA, Chi A, Lim ST, Bernard-Trifilo JA, Ilic D, Stupack DG, Cheresh DA, Schlaepfer DD. Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors. Oncogene. 2006;25:5969–5984. [PubMed]
71. Mitra SK, Schlaepfer DD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006;18:516–523. [PubMed]
72. Ilic D, Almeida EA, Schlaepfer DD, Dazin P, Aizawa S, Damsky CH. Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. J Cell Biol. 1998;143(2):547–560. [PMC free article] [PubMed]
73. Lim ST, Chen XL, Lim Y, Hanson DA, Vo TT, Howerton K, Larocque N, Fisher SJ, Schlaepfer DD, Ilic D. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell. 2008;29(1):9–22. [PMC free article] [PubMed]
74. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323–31. [PubMed]
75. Farmer G, Bargonetti J, Zhu H, Friedman P, Prywes R, Prives C. Wild-type p53 activates transcription in vitro. Nature. 1992;358(6381):83–86. [PubMed]
76. Bouchet BP, de Fromentel CC, Puisieux A, Galmarini CM. p53 as a target for anti-cancer drug development. Crit Rev Oncol Hematol. 2006;58(3):190–207. [PubMed]
77. Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowitz S, Willson JK, Hamilton S, Vogelstein B. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 1990;50(23):7717–7722. [PubMed]
78. Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B. Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature. 1992;355(6363):846–847. [PubMed]
79. Hollstein M, Hergenhahn M, Yang Q, Bartsch H, Wang ZQ, Hainaut P. New approaches to understanding p53 gene tumor mutation spectra. Mutat Res. 1999;431(2):199–209. [PubMed]
80. Willis AC, Chen X. The promise and obstacle of p53 as a cancer therapeutic agent. Curr Mol Med. 2002;2(4):329–345. [PubMed]
81. Wang W, Rastinejad F, El-Deiry WS. Restoring p53-dependent tumor suppression. Cancer Biol Ther. 2003;2(4 Suppl 1):S55–63. [PubMed]
82. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–767. [PubMed]
83. Giaccia AJ, Kastan MB. The complexity of p53 modulation. emerging patterns from divergent signals. Genes Dev. 1998;12(19):2973–2983. [PubMed]
84. Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem. 2002;277(5):3247–3257. [PubMed]
85. Wu Y, Mehew JW, Heckman CA, Arcinas M, Boxer LM. Negative regulation of bcl-2 expression by p53 in hematopoietic cells. Oncogene. 2001;20(2):240–251. [PubMed]
86. Taylor WR, Stark GR. Regulation of the G2/M transition by p53. Oncogene. 2001;20(15):1803–1815. [PubMed]
87. Krause K, Wasner M, Reinhard W, Haugwitz U, Dohna CL, Mossner J, Engeland K. The tumour suppressor protein p53 can repress transcription of cyclin B. Nucleic Acids Res. 2000;28(22):4410–4418. [PMC free article] [PubMed]
88. Johnsen JI, Aurelio ON, Kwaja Z, Jorgensen GE, Pellegata NS, Plattner R, Stanbridge EJ, Cajot JF. p53-mediated negative regulation of stathmin/Op18 expression is associated with G(2)/M cell-cycle arrest. Int J Cancer. 2000;88(5):685–691. [PubMed]
89. Murphy M, Hinman A, Levine AJ. Wild-type p53 negatively regulates the expression of a microtubule-associated protein. Genes Dev. 1996;10(23):2971–2980. [PubMed]
90. Benoit V, de Moraes E, Dar NA, Taranchon E, Bours V, Hautefeuille A, Taniere P, Chariot A, Scoazec JY, de Moura Gallo CV, Merville MP, Hainaut P. Transcriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB. Oncogene. 2006;25(42):5708–5718. [PubMed]
91. Wei CL, Wu Q, Vega VB, Chiu KP, Ng P, Zhang T, Shahab A, Yong HC, Fu Y, Weng Z, Liu J, Zhao XD, Chew JL, Lee YL, Kuznetsov VA, Sung WK, Miller LD, Lim B, Liu ET, Yu Q, Ng HH, Ruan Y. A global map of p53 transcription-factor binding sites in the human genome. Cell. 2006;124(1):207–219. [PubMed]
92. Stewart A, Ham C, Zachary I. The focal adhesion kinase amino-terminal domain localises to nuclei and intercellular junctions in HEK 293 and MDCK cells independently of tyrosine 397 and the carboxyterminal domain. Biochem Biophys Res Commun. 2002;299(1):62–73. [PubMed]
93. Jones G, Stewart G. Nuclear import of N-terminal FAK by activation of the FcepsilonRI receptor in RBL-2H3 cells. Biochem Biophys Res Commun. 2004;314(1):39–45. [PubMed]
94. Lobo M, Zachary I. Nuclear localization and apoptotic regulation of an amino-terminal domain focal adhesion kinase fragment in endothelial cells. Biochem Biophys Res Commun. 2000;276(3):1068–1074. [PubMed]
95. Chipuk JE, Green DR. Cytoplasmic p53. Bax and Forward. Cell Cycle. 2004;3(4):429–431. [PubMed]
96. Golubovskaya V, Finch R, Zheng M, Kurenova EV, Cance WG. The 7 amino-acid site in the proline-rich region of the N-terminal domain of p53 is involved in interaction with FAK and is critical for p53 functioning. Biochem J. 2008;411:151–160. [PubMed]
97. Han EK, McGonigal T, Wang J, Giranda VL, Luo Y. Functional analysis of focal adhesion kinase (FAK) reduction by small inhibitory RNAs. Anticancer Res. 2004;24(6):3899–3905. [PubMed]
98. Choi HS, Wang Z, Richmond W, He X, Yang K, Jiang T, Karanewsky D, Gu XJ, Zhou V, Liu Y, Che J, Lee CC, Caldwell J, Kanazawa T, Umemura I, Matsuura N, Ohmori O, Honda T, Gray N, He Y. Design and synthesis of 7H-pyrrolo[2,3-d]pyrimidines as focal adhesion kinase inhibitors. Part 2. Bioorg Med Chem Lett. 2006;16(10):2689–2692. [PubMed]
99. Shi Q, Hjelmeland AB, Keir ST, Song L, Wickman S, Jackson D, Ohmori O, Bigner DD, Friedman HS, Rich JN. A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth. Mol Carcinog. 2007 [PubMed]
100. Golubovskaya VM, Virnig C, Cance WG. TAE226-Induced apoptosis in breast cancer cells with overexpressed Src or EGFR. Mol Carcinog. 2007;46(6):488–96. [PubMed]
101. Beierle EA, Trujillo A, Nagaram A, Golubovskaya VM, Cance WG, Kurenova EV. TAE226 inhibits human neuroblastoma cell survival. Cancer Invest. 2008;26(2):145–151. [PubMed]
102. Liu W, Bloom DA, Cance WG, Kurenova EV, Golubovskaya VM, Hochwald SN. Fak And Igf-Ir Interact To Provide Survival Signals In Human Pancreatic Adenocarcinoma Cells. Carcinogenesis. 2008;29(6):1096–107. [PMC free article] [PubMed]
103. Slack-Davis JK, Martin KH, Tilghman RW, Iwanicki M, Ung EJ, Autry C, Luzzio MJ, Cooper B, Kath JC, Roberts WG, Parsons JT. Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007;282(20):14845–14852. [PubMed]
104. Roberts WG, Ung E, Whalen P, Cooper B, Hulford C, Autry C, Richter D, Emerson E, Lin J, Kath J, Coleman K, Yao L, Martinez-Alsina L, Lorenzen M, Berliner M, Luzzio M, Patel N, Schmitt E, LaGreca S, Jani J, Wessel M, Marr E, Griffor M, Vajdos F. Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res. 2008;68(6):1935–1944. [PubMed]
105. Bagi CM, Roberts GW, Andresen CJ. Dual focal adhesion kinase/Pyk2 inhibitor has positive effects on bone tumors. implications for bone metastases. Cancer. 2008;112(10):2313–21. [PubMed]
106. Vassilev LT. p53 Activation by small molecules. application in oncology. J Med Chem. 2005;48(14):4491–4499. [PubMed]
107. Akhter SA, Luttrell LM, Rockman HA, Iaccarino G, Lefkowitz RJ, Koch WJ. Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science. 1998;280(5363):574–577. [PubMed]
108. Aramburu J, Yaffe MB, Lopez-Rodriguez C, Cantley LC, Hogan PG, Rao A. Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science. 1999;285(5436):2129–33. [PubMed]
109. May MJ, D’Acquisto F, Madge LA, Glockner J, Pober JS, Ghosh S. Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science. 2000;289(5484):1550–1554. [PubMed]
110. van Rooij E, Doevendans PA, de Theije CC, Babiker FA, Molkentin JD, de Windt LJ. Requirement of nuclear factor of [PubMed]
111. Chen YN, Sharma SK, Ramsey TM, Jiang L, Martin MS, Baker K, Adams PD, Bair KW, Kaelin WG., Jr Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc Natl Acad Sci U S A. 1999;96(8):4325–4329. [PubMed]
112. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, Wang YT, Salter MW, Tymianski M. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science. 2002;298(5594):846–850. [PubMed]
113. Lim ST, Miller NL, Nam JO, Chen XL, Lim Y, Schlaepfer DD. PYK2 inhibition of p53 as an adaptive and intrinsic mechanism facilitating cell proliferation and survival. J Biol Chem. 2009 [Epub ahead of print] [PMC free article] [PubMed]
114. Golubovskaya VM, Nyberg C, Zheng M, Kweh F, Magis A, Ostrov D, Cance WG. A Small Molecule Inhibitor, 1,2,4,5-Benzenetetraamine Tetrahydrochloride, Targeting the Y397 Site of Focal Adhesion Kinase Decreases Tumor Growth. J Med Chem. 2008;51(23):7405–7416. [PMC free article] [PubMed]
115. Golubovskaya VM, Conway-Dorsey K, Edmiston SN, Tse CK, Lark AA, Livasy CA, Moore D, Millikan RC, Cance WG. FAK overexpression and p53 mutations are highly correlated in human breast cancer. Int J Cancer. 2009;125(7):1735–1738. [PMC free article] [PubMed]