The Nucleus-Localized Epidermal Growth Factor Receptor Is SUMOylated.

The epidermal growth factor receptor (EGFR) plays important roles in normal and cancer cell growth. The EGFR has principally two different signaling pathways: the canonical kinase route induced at the plasma membrane resulting in an intracellular phosphorylation cascade via MAPKs and PI3K and the more recently discovered pathway by which the receptor functions as a transcriptional co-activator inside the cell nucleus. Full length EGFR translocates to the inner nuclear membrane, via the endoplasmic reticulum, through association with the sec61ß translocon. The c-myc (MYC) and cyclin D1 (CNND1) genes represent two target genes for nuclear EGFR (nEGFR). Here we show that EGFR is SUMOylated and that the SUMO-1-modified receptors are almost unexceptionally nuclear. Co-immunoprecipitation experiments suggest that EGFR is multi-SUMOylated. Using two mass spectrometry-based strategies (matrix-assisted laser desorption ionization time of flight and electrospray ionization liquid chromatography with tandem mass spectrometry), lysine 37 was identified as a SUMO-1-modified residue by both methods. A lysine 37 site mutant (K37R) was transfected into EGFR deficient cells. Total SUMOylation of EGFR was not altered in the K37R-transfected cells, confirming the presence of other SUMOylation sites. To gain preliminary insight into the possible functional role of EGFR SUMOylation, we compared the effect of expression of the wild-type EGFR with the K37R mutant on promoter activity and expression of CMYC and CNND1. Our results indicate that SUMO-1 modification may affect the transcriptional activity of EGFR, which might have additional impact on, e.g., cancer progression.

Adherence to inhaled corticosteroid therapy and treatment escalation in the Swedish adult asthma population.

BACKGROUND: Patients with uncontrolled asthma should be evaluated for medication adherence. This study aimed to identify characteristics associated with poor adherence to inhaled corticosteroids (ICS) and to explore adherence prior to treatment escalation. METHODS: This nationwide longitudinal cohort study included adult asthma patients (n = 30880) with a healthcare visit including Asthma Control Test (ACT) and registered in the Swedish National Airway Register between 1 July 2017 and 28 February 2019 (index date). Patient data was crosslinked to other national registers. Treatment steps two years pre- and one year post-index, were identified by prescribed drugs. Poor adherence was defined as Medication Possession Ratio <80 %. RESULTS: Poor adherence was identified in 73 % of patients in treatment steps 2-5, where of 35 % had uncontrolled asthma (ACT≤19). In adjusted models, poor adherence was associated with better disease control; ACT≤19 (OR 0.78, 95 % CI 0.71-0.84), short-acting ß2-agonist (SABA) overuse (0.69, 0.61-0.79) and exacerbations (0.79, 0.70-0.89) in steps 2-3. Among patients with uncontrolled asthma, poor adherence was associated with SABA overuse (1.71, 1.50-1.95), exacerbations (1.29, 1.15-1.46), current smoking (1.38, 1.21-1.57) and inversely associated with asthma management education (0.85, 0.78-0.93. Similar results were observed in steps 4-5. When investigating post-index treatment, 53 % remained stationary, 30 % stepped down and 17 % escalated treatment. Prior to escalation, 49 % had poor adherence. CONCLUSIONS: Poor ICS adherence was associated with better asthma control. Among uncontrolled patients, poor adherence was associated with SABA overuse and exacerbations. Our result highlights the importance of asthma management education to improve adherence in uncontrolled patients.