Table 2.

HER signaling regulation.

Regulation mechanism	Effect on signaling	Mediators and mechanisms
Positive feedback loops	Prolong active signaling	Hetero-dimers containing HER2 often evade negative regulation. This is due to production of local EGF-like ligands and angiogenic factors upon activation of receptor
Negative feedback loops	Reduction in number of receptors	Multiple mechanisms involved: post-translational modifications, compartmentalization, catalytic inactivation, and steric hindrance. Pre-existing attenuators primarily control receptor phosphorylation and degradation. For example, density-enhanced phosphatase-1 (DEP-1) dephosphorylates HER1/EGFR
Buffering	Up-regulation/down-regulation	Heat-shock protein-90 (HSP90) is the most significant protein involved. When bound to HER2 it acts as a molecular switch – regulating heterodimer formation, catalytic function, and protein stability