Abstract
While multiple post-translational modifications have been reported to regulate the function of epidermal growth factor receptor (EGFR), the effect of protein methylation on its function has not been well characterized. In this study, we show that WHSC1L1 mono-methylates lysine 721 in the tyrosine kinase domain of EGFR, and that this methylation leads to enhanced activation of its downstream ERK cascade without EGF stimulation. We also show that EGFR K721 mono-methylation not only affects the function of cytoplasmic EGFR, but also that of nuclear EGFR. WHSC1L1-mediated methylation of EGFR in the nucleus enhanced its interaction with PCNA in squamous cell carcinoma of the head and neck (SCCHN) cells and resulted in enhanced DNA synthesis and cell cycle progression. Overall, our study demonstrates the multifaceted oncogenic function of the protein lysine methyltransferase WHSC1L1 in SCCHN, which is mediated through direct non-histone methylation of the EGFR protein with effects both in its cytoplasmic and nuclear functions.
Highlights
The epidermal growth factor receptor (EGFR) belongs to the well characterized family of receptor tyrosine kinases (RTK) and is known to play important roles in normal development as well as cancer pathogenesis through promotion of cell proliferation, invasion, migration, metastasis and angiogenesis[1,2,3,4]
We have showed that the protein lysine methyltransferase Wolf-Hirschhorn Syndrome Candidate 1-Like 1 (WHSC1L1) mono-methylates EGFR at lysine K721 in its tyrosine kinase domain, and leads to constitutive enhancement of the RAS-RAF-MEK-ERK pathway through augmentation of phospho-Y1148 and phospho-Y1173 in SCCHN cells even without EGF stimulation
We showed that WHSC1L1-mediated K721 EGFR mono-methylation enhanced its interaction with proliferating cell nuclear antigen (PCNA)
Summary
The epidermal growth factor receptor (EGFR) belongs to the well characterized family of receptor tyrosine kinases (RTK) and is known to play important roles in normal development as well as cancer pathogenesis through promotion of cell proliferation, invasion, migration, metastasis and angiogenesis[1,2,3,4]. Liao et al.[14] reported that PRMT1-mediated methylation of R198/200 in the extracellular domain of EGFR enhances its binding to EGF and its homodimerization, and activates both the RAS-RAF-MEK-ERK and the PI3K-AKT growth-signaling pathways in colon cancer cells. Nuclear EGFR exists in a full-length EGFR form and maintains its tyrosine kinase activity In the nucleus, it interacts with E2F1, RNA helicase A, DNA-dependent protein kinase (DNA-PK), signal transducer and activator of transcription 3 (STAT3), STAT5 and proliferating cell nuclear antigen (PCNA)[18,19]. We recently showed that WHSC1L1 was significantly overexpressed in SCCHN tissues compared to normal epithelium, and its siRNA-mediated knockdown significantly decreased cell viability in SCCHN cells[29]
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