Recent progress on FAK inhibitors with dual targeting capabilities for cancer treatment

Wu, Xianbo; Wang, Jie; Liang, Qi; Tong, Rongsheng; Huang, Jianli; Yang, Xinwei; Xu, Yunyun; Wang, Wenjing; Sun, Minghan; Shi, Jianyou

doi:10.1016/j.biopha.2022.113116

Cited by 29 publications

(16 citation statements)

References 150 publications

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“…Three proline-rich regions (PRRs) are anchored to the linkage region between these structural domains. Phosphorylation occurs at several important tyrosine residues, including the autophosphorylation site Tyr397, Tyr576/577 in the activation loop of the kinase structural domain, and Tyr861, Tyr925, and Tyr1007 in the C-terminal structural domain ( Wu et al, 2022 ). It is well known that both the N- and C-terminal structural domains mediate the interaction of FAK with other proteins essential for activating its kinase structural domain and regulating different cellular functions.…”

Section: Characteristics Of the Focal Adhesion Kinase Moleculementioning

confidence: 99%

Functional and clinical characteristics of focal adhesion kinases in cancer progression

Zhang

Li²,

Jiao³

et al. 2022

Front. Cell Dev. Biol.

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and an adaptor protein that primarily regulates adhesion signaling and cell migration. FAK promotes cell survival in response to stress. Increasing evidence has shown that at the pathological level, FAK is highly expressed in multiple tumors in several systems (including lung, liver, gastric, and colorectal cancers) and correlates with tumor aggressiveness and patient prognosis. At the molecular level, FAK promotes tumor progression mainly by altering survival signals, invasive capacity, epithelial-mesenchymal transition, the tumor microenvironment, the Warburg effect, and stemness of tumor cells. Many effective drugs have been developed based on the comprehensive role of FAK in tumor cells. In addition, its potential as a tumor marker cannot be ignored. Here, we discuss the pathological and pre-clinical evidence of the role of FAK in cancer development; we hope that these findings will assist in FAK-based clinical studies.

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Section: Characteristics Of the Focal Adhesion Kinase Moleculementioning

confidence: 99%

Functional and clinical characteristics of focal adhesion kinases in cancer progression

Zhang

Li²,

Jiao³

et al. 2022

Front. Cell Dev. Biol.

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“…FAK or protein tyrosine kinase 2 is a non-receptor and non-membrane-associated protein tyrosine kinase activated at cell-matrix adhesion sites and clustering of integrins by autophosphorylation (at Tyr397), SRC, and other tyrosine kinases ( 35 ). FAK regulates cell migration, adhesion, and survival by transferring signals from the extracellular matrix to the cytoplasm via integrins ( 36 ). Therefore, under hypoxia conditions, both EGFR and FAK in the HIF-1/ErbB signaling pathway may promote cell adhesion, leading endometrial epithelial cells to adhere to trophoblast cells.…”

Section: Discussionmentioning

confidence: 99%

miRNA-150_R-1 mediates the HIF-1/ErbB signaling pathway to regulate the adhesion of endometrial epithelial cells in cows experiencing retained placenta

Li²,

Wang³

et al. 2022

Front. Vet. Sci.

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Retained placenta (RP) refers to reproductive disorders caused by the failure of fetal membranes to be expelled 12 h after delivery in dairy cows. Postpartum adhesion of the fetal membranes to the uterus causes diseases such as mastitis or endometritis, which threatening the profitability of the dairy industry. Emerging evidence suggests that micro RNAs (miRNAs) play crucial roles in various processes, such as the occurrence and progression of fetal membranes discharge. However, the molecular mechanisms of miRNAs in RP remain unknown. In this study, we performed RNA-sequencing to characterize the expression profiles of mRNAs and miRNAs in caudal vein blood samples of postpartum Holstein cows whose fetal membranes were discharged normally or retained to identify RP-related genes and evaluate their molecular mechanisms. We identified 44 differentially expressed miRNAs (19 upregulated and 25 downregulated) and 706 differentially expressed mRNAs (325 upregulated and 381 downregulated) in the RP group compared to the normal fetal membranes discharge group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed that differentially expressed mRNAs were mainly enriched in the extracellular matrix, cell adhesion, and autoimmunity-related biological processes or pathways. Further analyses using RNA-sequencing, a dual luciferase reporter system, quantitative reverse transcription-PCR, immunofluorescence, and western blotting verified that endothelial PAS domain protein 1 (EPAS1) is regulated by miR-150_R-1 in endometrial epithelial cells. We demonstrated the relationship between EPAS1 and RP and confirmed that EPAS1 is upregulated in the blood and placenta of cows that experience RP. Further, we proposed a model of the miRNA-mRNA negative regulatory network mediated by the HIF-1/ErbB signaling pathway to show its regulatory role in RP.

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“…FAK1 has a number of crucial roles in the regulation of angiogenesis, cell adhesion, apoptosis, migration, proliferation, and spreading, as well as in the control of cell cycle progression, formation, and disassembly of focal adhesions and cell protrusions, and the reorganization of the actin cytoskeleton [191]. Among the important activities of FAK1 are regulation of integrin and growth factor signaling pathways [192]. This kinase is most known for its role in many invasive and metastatic cancers, such as breast cancer, lung cancer, neck cancer, ovarian cancer, and prostate cancer, where high FAK levels are associated with poor prognosis.…”

Section: Fak1mentioning

confidence: 99%

Liaisons dangereuses: Intrinsic Disorder in Cellular Proteins Recruited to Viral Infection-Related Biocondensates

Bianchi

Brocca

Longhi

et al. 2023

IJMS

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Liquid–liquid phase separation (LLPS) is responsible for the formation of so-called membrane-less organelles (MLOs) that are essential for the spatio-temporal organization of the cell. Intrinsically disordered proteins (IDPs) or regions (IDRs), either alone or in conjunction with nucleic acids, are involved in the formation of these intracellular condensates. Notably, viruses exploit LLPS at their own benefit to form viral replication compartments. Beyond giving rise to biomolecular condensates, viral proteins are also known to partition into cellular MLOs, thus raising the question as to whether these cellular phase-separating proteins are drivers of LLPS or behave as clients/regulators. Here, we focus on a set of eukaryotic proteins that are either sequestered in viral factories or colocalize with viral proteins within cellular MLOs, with the primary goal of gathering organized, predicted, and experimental information on these proteins, which constitute promising targets for innovative antiviral strategies. Using various computational approaches, we thoroughly investigated their disorder content and inherent propensity to undergo LLPS, along with their biological functions and interactivity networks. Results show that these proteins are on average, though to varying degrees, enriched in disorder, with their propensity for phase separation being correlated, as expected, with their disorder content. A trend, which awaits further validation, tends to emerge whereby the most disordered proteins serve as drivers, while more ordered cellular proteins tend instead to be clients of viral factories. In light of their high disorder content and their annotated LLPS behavior, most proteins in our data set are drivers or co-drivers of molecular condensation, foreshadowing a key role of these cellular proteins in the scaffolding of viral infection-related MLOs.

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Recent progress on FAK inhibitors with dual targeting capabilities for cancer treatment

Cited by 29 publications

References 150 publications

Functional and clinical characteristics of focal adhesion kinases in cancer progression

Functional and clinical characteristics of focal adhesion kinases in cancer progression

miRNA-150_R-1 mediates the HIF-1/ErbB signaling pathway to regulate the adhesion of endometrial epithelial cells in cows experiencing retained placenta

Liaisons dangereuses: Intrinsic Disorder in Cellular Proteins Recruited to Viral Infection-Related Biocondensates

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