The role of Rak in the regulation of stability and function of BRCA1

Abstract

BRCA1 is an important player in the DNA damage response signaling, and its deficiency results in genomic instability. A complete loss or significantly reduced BRCA1 protein expression is often found in sporadic breast cancer cases despite the absence of genetic or epigenetic aberrations, suggesting the existence of other regulatory mechanisms controlling BRCA1 protein expression. Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. In addition, Rak deficiency confers cellular sensitivity to DNA damaging agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Overall, our findings highlight a critical role of Rak in the maintenance of genomic stability, at least in part, through protecting BRCA1 and provide novel treatment strategies for patients with breast tumors lacking Rak.

Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology

“…More recently, breast cancer susceptibility gene 1 (BRCA1) was identified as a bona fide FRK substrate [41]. The effect of BRCA1 phosphorylation by FRK is reminiscent of the regulation of PTEN stability by FRK, described earlier.…”

“…Another study reported elevated FRK mRNA levels in two out of six breast tumour tissue samples analysed. A very recent study revealed FRK expression to positively correlate with BRCA1 expression in tissue samples corresponding to invasive ductal breast carcinoma cases, as determined via IHC analyses [41]. Further, the study reported FRK as an under-expressed protein in nearly 20 % cases examined (14 out of 70 cases) [41].…”

“…A very recent study revealed FRK expression to positively correlate with BRCA1 expression in tissue samples corresponding to invasive ductal breast carcinoma cases, as determined via IHC analyses [41]. Further, the study reported FRK as an under-expressed protein in nearly 20 % cases examined (14 out of 70 cases) [41]. Nonetheless, the limited nature of this and other screening analyses renders it difficult to provide a clear picture of FRK expression across various breast cancer subtypes or between normal and tumour-derived cell lines and tissues.…”

“…Lately, BRCA1 was identified as a substrate of FRK [41]. FRK was shown to phosphorylate BRCA1 specifically on Y1552 and protect BRCA1 from UBE2-induced degradation (Fig.…”

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

“…In HepG2, we observed a partial LOH for the 5' portion FRK (Table S3). Since its discovery in 1993, FRK was first attributed as a tumor suppressor (Craven et al 1995;Oberg-Welsh et al 1998;Brauer and Tyner 2009;Kim et al 2015); however, further investigations show that FRK appears to play a tissue-specific oncogenic role in liver, pancreatic, breast and brain cancers and has been proposed as a therapeutic target (Goel and Lukong 2016). Interestingly, it was shown ectopic overexpression of FRK in HepG2 had no effect on cell proliferation, while this overexpression results in a significant growth reduction (p-value < 0.05) was observed in HepG2 cells with FRK-knockdown .…”