Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation

Ligand-dependent oligomerization of receptor tyrosine kinases (RTKs) results in their activation through highly specific conformational changes in the extracellular and intracellular receptor domains. These conformational changes are unique for each RTK subfamily, limiting cross-activation between unrelated RTKs. The proto-oncogene MET receptor tyrosine kinase overcomes these structural constraints and phosphorylates unrelated RTKs in numerous cancer cell lines. The molecular basis for these interactions is unknown. We investigated the mechanism by which MET phosphorylates the human epidermal growth factor receptor-3 (HER3 or ERBB3), a catalytically impaired RTK whose phosphorylation by MET has been described as an essential component of drug resistance to inhibitors targeting EGFR and HER2. We find that in untransformed cells, HER3 is not phosphorylated by MET in response to ligand stimulation, but rather to increasing levels of MET expression, which results in ligand-independent MET activation. Phosphorylation of HER3 by its canonical co-receptors, EGFR and HER2, is achieved by engaging an allosteric site on the HER3 kinase domain, but this site is not required when HER3 is phosphorylated by MET. We also observe that HER3 preferentially interacts with MET during its maturation along the secretory pathway, before MET is post translationally processed by cleavage within its extracellular domain. This results in accumulation of phosphorylated HER3 in the Golgi apparatus. We further show that in addition to HER3, MET phosphorylates other RTKs in the Golgi, suggesting that this mechanism is not limited to HER3 phosphorylation. These data demonstrate a link between MET overexpression and its aberrant activation in the Golgi endomembranes and suggest that non-canonical interactions between MET and other RTKs occur during maturation of receptors. Our study highlights a novel aspect of MET signaling in cancer that would not be accessible to inhibition by therapeutic antibodies

Quantitative assessment of systolic left ventricular function with speckle-tracking echocardiography in adult patients with repaired aortic coarctation

Despite successful aortic coarctation (CoA) repair, systemic hypertension often recurs which may influence left ventricular (LV) function. We aimed to detect early LV dysfunction using LV global longitudinal strain (GLS) in adults with repaired CoA, and to identify associations with patient and echocardiographic characteristics. In this cross-sectional study, patients with repaired CoA and healthy controls were recruited prospectively. All subjects underwent echocardiography, ECG and blood sampling within 1 day. With speckle-tracking echocardiography, we assessed LV GLS on the apical four-, three- and two-chamber views. We included 150 subjects: 75 patients (57 % male, age 33.4 ± 12.8 years, age at repair 2.5 [IQR: 0.1–11.1] years) and 75 healthy controls of similar sex and age. LV GLS was lower in patients than in controls (−17.1 ± 2.3 vs. −20.2 ± 1.6 %, P < 0.001). Eighty percent of the patients had a normal LV ejection fraction, but GLS was still lower than in controls (P < 0.001). In patients, GLS correlated with systolic and diastolic blood pressure (r = 0.32, P = 0.009; r = 0.31, P = 0.009), QRS duration (r = 0.34, P = 0.005), left atrial dimension (r = 0.27, P = 0.029), LV mass (r = 0.30, P = 0.014) and LV ejection fraction (r = −0.48, P < 0.001). Patients with either associated cardiac lesions, multiple cardiac interventions or aortic valve replacement had lower GLS than patients without. Although the majority of adults with repaired CoA seem to have a normal systolic LV function, LV GLS was decreased. Higher blood pressure, associated cardiac lesions, and larger left atrial dimension are related with lower GLS. Therefore, LV GLS may be used as objective criterion for early detection of ventricular dysfunction. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10554-016-0838-8) contains supplementary material, which is available to authorized users