FER-mediated phosphorylation and PIK3R2 recruitment on IRS4 promotes AKT activation and tumorigenesis in ovarian cancer cells

Abstract

Tyrosine phosphorylation, orchestrated by tyrosine kinases and phosphatases, modulates a multi-layered signaling network in a time- and space-dependent manner. Dysregulation of this post-translational modification is inevitably associated with pathological diseases. Our previous work has demonstrated that non-receptor tyrosine kinase FER is upregulated in ovarian cancer, knocking down which attenuates metastatic phenotypes. However, due to the limited number of known substrates in the ovarian cancer context, the molecular basis for its pro-proliferation activity remains enigmatic. Here, we employed mass spectrometry and biochemical approaches to identify insulin receptor substrate 4 (IRS4) as a novel substrate of FER. FER engaged its kinase domain to associate with the PH and PTB domains of IRS4. Using a proximity-based tagging system in ovarian carcinoma-derived OVCAR-5 cells, we determined that FER-mediated phosphorylation of Tyr779 enables IRS4 to recruit PIK3R2/p85β, the regulatory subunit of PI3K, and activate the PI3K-AKT pathway. Rescuing IRS4-null ovarian tumor cells with phosphorylation-defective mutant, but not WT IRS4 delayed ovarian tumor cell proliferation both in vitro and in vivo. Overall, we revealed a kinase-substrate mode between FER and IRS4, and the pharmacological inhibition of FER kinase may be beneficial for ovarian cancer patients with PI3K-AKT hyperactivation.

Identification of a novel SH3PXD2B::FER fusion in a case of plexiform myofibroblastic tumor and review of the literature

“…The role of FER kinase as an independent prognostic factor was investigated in breast cancer where elevated FER levels correlate with high-grade breast cancer types. 14 Overexpression of FER is also associated with poor clinical outcomes in renal cell carcinoma, 15 non-small cell lung cancer, 16 lung adenocarcinoma, 17 ovarian cancer cells, 18 and hepatocellular carcinoma. 19,20 Few genomic rearrangements involving FER kinase have been reported in the literature to date.…”

HDAC inhibitors target IRS4 to enhance anti-androgen receptor (AR) therapy in AR-positive triple negative breast cancer

“…IRSs can activate PI3K/Akt signalling downstream of the insulin-like growth factor receptor to promote tumour growth. [40][41][42] In trastuzumab-resistant breast cancer, IGF2/IGF-1R/IRS1 signalling has been demonstrated to be signi cantly activated via disruption of FOXO3a-miRNA negative feedback inhibition, providing a predictive biomarker and potential treatment strategy to overcome Herceptin resistance. 43 In ductal carcinoma in situ, high IRS1 with low IRS2 expression could predict the responsiveness and effectiveness of chemotherapy in breast cancer.…”

Fer and FerT: A New Regulatory Link between Sperm and Cancer Cells

“…There is contradiction in the literature regarding the regulation of CatSper by PKA. The group of Orta suggested that CatSper is regulated by PKA [ 65 ], whereas the group of Wang claim that CatSper is not activated by PKA [ 66 ]. We claim that CatSper is regulated/inhibited by Fer which is localized downstream to PKA (see model Figure 2 ), suggesting that PKA regulates CatSper indirectly via activation of Fer which inhibits CatSper.…”