Endothelial Cell Signaling During Wound Healing
John J. Lemasters, Constance Oliver in Cell Biology of Trauma, 2020
The activation of FAK may support focal adhesion formation by phosphorylating other cytoskeletal proteins directly. One candidate is the vinculin-binding protein paxillin,85 which is tyrosine phosphorylated during integrin-mediated cell adhesion.68,69 FAK and paxillin colocalize in focal adhesions and have similar tyrosine phosphorylation patterns during development and neuropeptide stimulation.107,108 The phosphotyrosine content of paxillin also correlates with FAK expression in cells that overexpress the focal adhesion kinase.87 This correlation has also been observed for tensin,87 another focal adhesion protein that is tyrosine phosphorylated during integrin-mediated cell-ECM adhesion.109 Tensin is known to contain an SH2 domain,110 and this may facilitate a binding interaction with paxillin or FAK. Finally, a 130-kDa nonkinase phosphoprotein has been described in fibroblasts that is tyrosine phosphorylated during integrin-mediated cell adhesion,111 and may represent another FAK substrate.
Resistance Exercise Training and The Regulation of Muscle Protein Synthesis
Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse in The Routledge Handbook on Biochemistry of Exercise, 2020
Although initially it was believed that MPS could be entirely regulated through an mTORC1-dependent mechanism, recent research predominantly in rodent skeletal muscle has suggested MPS can still be elevated in response to anabolic stimuli in the presence of mTORC1 inhibitors (70, 111). Therefore, it has now been postulated that several mTORC1-independent mechanisms may be implicated in the regulation of protein synthesis, the majority of which appear to be coordinated through the mitogen-activated protein kinase/extracellular signal–regulated kinases 1/2 (MAPK/ERK1/2) pathway (22). In contrast to mTORC1-dependent mechanisms, which are sensitive to both mechanical and nutrient stimuli (59, 61, 109), this pathway seems to be predominantly mechanically regulated in human skeletal muscle (61). This intricate signalling pathway is initiated at the cell membrane via the binding of a ligand to its receptor or via the activation of focal adhesion kinase or integrins by mechanical stimuli (89, 91). Following this, several phosphorylation events occur, leading to the activation of ERK1/2 (50, 83, 96), a kinase which has several substrates implicated in the control of protein synthesis.
Liposomes in the Delivery Of Antisense Oligonucleotides
Danilo D. Lasic in LIPOSOMES in GENE DELIVERY, 2019
Therapeutic studies of antisense sequence to focal adhesion kinase in human tumor lines in nude mice are under investigation (Huang et al., 1996). When 150 mM lipid and 100 mg/mL oligonucleotide solution were used, 10% of molecules were encapsulated. Different sterically stabilized liposomes were tried in order to encapsulate or bind to a partially cationic surface. Targeted liposomes containing Fab’ fragments attached to the far end of the PEG chain were also used. Physicochemical characteristics of complexes and their biological stability and interactability were also followed (Meyer et al. 1996).
Improved anticancer activity of betulinic acid on breast cancer through a grafted copolymer-based micelles system
Published in Drug Delivery, 2021
Xueju Qi, Cong Gao, Chuanjin Yin, Junting Fan, Xiaochen Wu, Chuanlong Guo
Tumor growth depends on angiogenesis and is affected by multiple signaling pathways. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays a basic role in signal transduction mediated by integrins and growth factors, and plays a vital role in cell migration and proliferation (Tavora et al. 2010; Chen et al. 2012). Moreover, tumor cells can release growth factors (e.g., VEGF) into the microenvironment, thereby activating the proliferation of vascular endothelial cells and inducing tumor metastasis (Pang et al. 2011; Bi et al. 2017). Recently, it was discovered that Hypoxia inducible factor-1 (HIF-1) directly regulates the expression of VEGF at the gene level and is an important regulator of malignant tumor-induced angiogenesis (Palazon et al. 2017). In this study, the expression of HIF-1 and VEGF was restrained by free BA as well as Soluplus-BA micelles, while Soluplus-BA micelles showed a more significant inhibitory effect. In addition, BA decreased FAK phosphorylation in HUVEC cells (Figure 7(C)). The angiogenesis inhibitory effect of BA may be accomplished by regulating the HIF-1/VEGF-FAK signaling pathway.
2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mostafa M. Elbadawi, Wagdy M. Eldehna, Amer Ali Abd El-Hafeez, Warda R. Somaa, Amgad Albohy, Sara T. Al-Rashood, Keli K. Agama, Eslam B. Elkaeed, Pradipta Ghosh, Yves Pommier, Manabu Abe
Focal adhesion kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase involved in signal transductions from cell adhesions to regulate different biological cell functions including survival and cell migration13,14. Also, it is activated and overexpressed in diverse cancer types controlling cancer proliferation, survival and metastasis. Thus, FAK has been identified as a promising druggable target for targeted cancer therapy. Currently, several FAK inhibitors, such as 2,4-diaminopyridine derivative GSK2256098 and 2,4-diaminopyrimidine derivative Defactinib (Figure 1), are currently being evaluated in clinical trials for cancer treatment, in addition to the 2,4-diaminopyrimidine derivative TAE-226 (Figure 1) which displayed potent antitumor impact in different cancer types in vivo and in vitro and usually used as a reference drug7,15,16. Noteworthy, it was established that the most affected colorectal cancer expressed high levels of EGFR and FAK that particularly correlated with tumour angiogenesis, cancer aggressiveness and poor prognosis17,18.
The Roles of Tissue Rigidity and Its Underlying Mechanisms in Promoting Tumor Growth
Published in Cancer Investigation, 2020
Muhammad Asyaari Zakaria, Nor Fadilah Rajab, Eng Wee Chua, Gayathri Thevi Selvarajah, Siti Fathiah Masre
Focal adhesion kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase that forms at ECM-integrin junctions. It acts like a “biosensor” to respond to extracellular changes, including increased tissue rigidity, and translate it into biochemical signals (14,85,86). The rate of FAK activation was found to be sensitive and dependent on the rigidity of the substrate and cytoskeletal pulling force. This finding by Bell and Terentjev (87) suggested an increase in FAK activation as tissue rigidity increases until it reaches plateau. Briefly, FAK was activated by phosphorylation at Tyr397 residue, necessary for Src kinase binding, which will finally lead to an additional phosphorylation at the other side of catalytic domain (Tyr407, Tyr576, Tyr577, Tyr861, and Tyr925) to complete FAK activation (88,89). Concurrently, FAK was activated upon interactions with integrins, cytokine receptors, G protein-coupled receptors, and growth factor receptors (90). FAK performs multiple cellular functions, such as regulating the assembly of numerous signaling proteins, as well as enabling cytoskeletal regulation by activation and inhibition of various small GTPase proteins such as Ras, Rac, Rho, and Cdc42 (91,92). Activation of these downstream targets, in particular Rho or ROCK, will then increase actomyosin contractility and regulate cellular phenotypes that favor tumor growth (93) as studied by Peng et al. (14) and Mierke et al. (17) which have shown that FAK is required for ROCK-induced cell migration in their rigid matrices.
Related Knowledge Centers
- Focal Adhesion
- P53
- Protein
- Extracellular Matrix
- Gene
- Kinase
- NON-Receptor Tyrosine Kinase
- Tyrosine Kinase
- Ptk2B
- Ferm Domain