» Articles » PMID: 31006845

Focal Adhesion Kinase (FAK) Phosphorylation is a Key Regulator of Embryonal Rhabdomyosarcoma (ERMS) Cell Viability and Migration

Overview
Specialty Oncology
Date 2019 Apr 23
PMID 31006845
Citations 7
Authors
Affiliations
Soon will be listed here.
Abstract

Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. Pathogenesis of RMS is associated with aggressive growth pattern and increased risk of morbidity and mortality. There are two main subtypes or RMS: embryonal and alveolar. The embryonal type is characterized by distinct molecular aberrations, including alterations in the activity of certain protein kinases. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a vital role in focal adhesion (FA) assembly to promote cytoskeleton dynamics and regulation of cell motility. It is regulated by multiple phosphorylation sites: tyrosine 397, Tyr 576/577, and Tyr 925. Tyrosine 397 is the autophosphorylation site that regulates FAK localization at the cell periphery to facilitate the assembly and formation of the FA complex. The kinase activity of FAK is mediated by the phosphorylation of Tyr 576/577 within the kinase domain activation loop. Aberrations of FAK phosphorylation have been linked to the pathogenesis of different types of cancers. In this regard, pY397 upregulation is linked to increase ERMS cell motility, invasion, and tumorigenesis.

Methods: In this study, we have used an established human embryonal muscle rhabdomyosarcoma cell line RD as a model to examine FAK phosphorylation profiles to characterize its role in the pathogenies of RMS.

Results: Our findings revealed a significant increase of FAK phosphorylation at pY397 in RD cells compared to control cells (hTERT). On the other hand, Tyr 576/577 phosphorylation levels in RD cells displayed a pronounced reduction. Our data showed that Y925 residue exhibited no detectable change. The in vitro analysis showed that the FAK inhibitor, PF-562271 led to G1 cell-cycle arrest induced cell death (IC, ~ 12 µM) compared to controls. Importantly, immunostaining analyses displayed a noticeable reduction of Y397 phosphorylation following PF-562271 treatment. Our data also showed that PF-562271 suppressed RD cell migration in a dose-dependent manner associated with a reduction in Y397 phosphorylation.

Conclusions: The data presented herein indicate that targeting FAK phosphorylation at distinct sites is a promising strategy in future treatment approaches for defined subgroups of rhabdomyosarcoma.

Citing Articles

Low concentrations of saracatinib promote definitive endoderm differentiation through inhibition of FAK-YAP signaling axis.

Ma R, Bi H, Wang Y, Wang J, Zhang J, Yu X Cell Commun Signal. 2024; 22(1):300.

PMID: 38816763 PMC: 11140888. DOI: 10.1186/s12964-024-01679-7.


Breast Cancer Prognosis Prediction and Immune Pathway Molecular Analysis Based on Mitochondria-Related Genes.

Luo W, Han Y, Li X, Liu Z, Meng P, Wang Y Genet Res (Camb). 2022; 2022:2249909.

PMID: 35707265 PMC: 9174003. DOI: 10.1155/2022/2249909.


Effects of Titanium Dioxide Nanoparticles on Cell Growth and Migration of A549 Cells under Simulated Microgravity.

Wang M, Li J, Zhang S, You Y, Zhu X, Xiang H Nanomaterials (Basel). 2022; 12(11).

PMID: 35683734 PMC: 9182076. DOI: 10.3390/nano12111879.


New Insights on the Nuclear Functions and Targeting of FAK in Cancer.

Pomella S, Cassandri M, Braghini M, Marampon F, Alisi A, Rota R Int J Mol Sci. 2022; 23(4).

PMID: 35216114 PMC: 8874710. DOI: 10.3390/ijms23041998.


Focal adhesion kinase inhibitors, a heavy punch to cancer.

Wu Y, Li N, Ye C, Jiang X, Luo H, Zhang B Discov Oncol. 2022; 12(1):52.

PMID: 35201485 PMC: 8777493. DOI: 10.1007/s12672-021-00449-y.


References
1.
RUYMANN F, Grovas A . Progress in the diagnosis and treatment of rhabdomyosarcoma and related soft tissue sarcomas. Cancer Invest. 2001; 18(3):223-41. DOI: 10.3109/07357900009031827. View

2.
Xie B, Zhao J, Kitagawa M, Durbin J, Madri J, Guan J . Focal adhesion kinase activates Stat1 in integrin-mediated cell migration and adhesion. J Biol Chem. 2001; 276(22):19512-23. DOI: 10.1074/jbc.M009063200. View

3.
Schaller M . Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim Biophys Acta. 2001; 1540(1):1-21. DOI: 10.1016/s0167-4889(01)00123-9. View

4.
Zhao J, Pestell R, Guan J . Transcriptional activation of cyclin D1 promoter by FAK contributes to cell cycle progression. Mol Biol Cell. 2001; 12(12):4066-77. PMC: 60776. DOI: 10.1091/mbc.12.12.4066. View

5.
Hsia D, Mitra S, Hauck C, Streblow D, Nelson J, Ilic D . Differential regulation of cell motility and invasion by FAK. J Cell Biol. 2003; 160(5):753-67. PMC: 2173366. DOI: 10.1083/jcb.200212114. View