Synuclein gamma protects HER2 and renders resistance to Hsp90 disruption.

Hsp90 is an important driver of stabilization and activation of several oncogenic proteins in many key pathways in oncogenesis, including HER2. The present study demonstrated that synuclein gamma (SNCG) prevents the protein degradation and protects the function of HER2 in the condition when the function of Hsp90 is blocked. Disruption of Hsp90 resulted in a significant degradation of HER2 and the loss of activity. However, SNCG completely recovered Hsp90 disruption-mediated losses of HER2 and the function. SNCG bound to HER2 in the presence and absence of Hsp90. Specifically, the C-terminal (Gln106-Asp127) of SNCG bound to the loop connecting αC helix and β4 sheet of the kinase domain of HER2. SNCG renders resistance to 17-AAG-induced tumor suppression in tumor xenograft. Crossing SNCG transgenic mice with HER2 mice stimulated HER2-induced tumor growth and rendered resistance to Hsp90 disruption. The present study indicates that SNCG protects Hsp90 client protein of HER2, and renders resistance to Hsp90 disruption.