Frk
FRK is a non-receptor tyrosine kinase in the BRK family kinases, distantly related to Src family kinases, and its biology centers on phosphorylation-dependent control of growth and signaling[1][2]. Mechanistically, FRK has been linked to PTEN stability, EGFR internalization, cyclin D1 nuclear accumulation, ITGB1/FAK signaling, and YAP ubiquitylation, placing it in cell-cycle, receptor-trafficking, adhesion, and Hippo-pathway research[3][4][5][6][7]. In disease models, FRK suppressed breast cancer cell proliferation and invasion, inhibited glioma growth or progression in several studies, but recurrent FRK-activating mutations drove STAT3 activation and proliferation in hepatocellular adenoma[3][5][6][7][8]. Compared with related isoforms, FRK/Rak/Gtk/Iyk/Bsk belongs to a conserved Brk/Srm/Frk/Src42A group that remains structurally distinct from c-Src and Fyn[2]. For experimental applications, FRK fusions in ALK-negative anaplastic large-cell lymphoma showed kinase targetability, and FRK-activating hepatocellular adenoma mutations showed sensitivity to Src inhibitors[8][9].
References:
- [1]. Goel RK, et al. Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology. Cancer Metastasis Rev. 2016 Jun;35(2):179-99. [Content Brief]
- [2]. Serfas MS, et al. Brk, Srm, Frk, and Src42A form a distinct family of intracellular Src-like tyrosine kinases. Oncol Res. 2003;13(6-10):409-19. [Content Brief]
- [3]. Yim EK, et al. Rak functions as a tumor suppressor by regulating PTEN protein stability and function. Cancer Cell. 2009 Apr 7;15(4):304-14. [Content Brief]
- [4]. Jin L, et al. The Rak/Frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor. Oncogene. 2014 Jan 16;33(3):326-35. [Content Brief]
- [5]. Hua L, et al. FRK suppresses the proliferation of human glioma cells by inhibiting cyclin D1 nuclear accumulation. J Neurooncol. 2014 Aug;119(1):49-58. [Content Brief]
- [6]. Wang J, et al. FRK suppresses human glioma growth by inhibiting ITGB1/FAK signaling. Biochem Biophys Res Commun. 2019 Oct 1;517(4):588-595. [Content Brief]
- [7]. Wang Y, et al. FRK inhibits glioblastoma progression via phosphorylating YAP and inducing its ubiquitylation and degradation by Siah1. Neuro Oncol. 2022 Dec 1;24(12):2107-2120. [Content Brief]
- [8]. Pilati C, et al. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell. 2014 Apr 14;25(4):428-41. [Content Brief]
- [9]. Hu G, et al. Targetable fusions of the FRK tyrosine kinase in ALK-negative anaplastic large cell lymphoma. Leukemia. 2018 Feb;32(2):565-569. [Content Brief]
