Targeting SIAH E3 Ligase Downstream of the HER2/Neu/RAS Signaling Pathway to Block Tumorigenesis and Metastasis of Highly Invasive Human Breast Cancer.

摘要

We have uncovered a novel mechanism of K-RAS and TGF beta; antagonism in human breast cancer. We showed that SMAD2/3/4 - the essential downstream mediators of TGFbeta; signaling, are new SIAH2 substrates. SIAH2 physically interacts with, ubiquitinates and degrades SMAD2/3/4 (but not SMAD1 - the downstream mediator of the BMP signaling pathway). We propose that the tumor promoting activity of K-RAS/SIAH2 may be mediated through the degradation of SMAD2/3/4 proteins and thus the relief of TGF beta;-dependent growth inhibition in response to K-RAS pathway activation. The identification of the SIAH2-mediated SMAD2/3/4 modulation downstream of K-RAS and TGF beta; signaling pathways may provide an additional mechanism to explain the well documented, but less understood K-RAS and TG Fbeta; antagonism described in normal development and oncogenesis. This novel mode of antagonistic interaction between the two opposing signaling pathways may promote the growth inhibitory action of the TGF beta; pathway and the growth-promoting activity of the K-RAS pathway in the genesis, progression and metastasis of human cancer. Since the substrate specificity of ubiquitin-mediated proteolysis is primarily determined by the E3 ligase, our results provide new insights into the role of enhanced proteolysis by SIAH2 in mediating the context-dependent ERBB/K-RAS-TGF beta; antagonism and context-dependent dynamic cross-talk in tumorigenesis and metastasis.