Molecular Cell n

rc stream signaling kinases they control are highly the Raf-MEK-ERK (MAPK) and PI3K-Akt kinase cascades (Yarden and Sliwkowski, 2001) and the actin cytoskeletonhomo- and hetero-oligomers. In the case of ErbB1, whose struc-ture has been studied in detail, ligand binding is thought to promote a conformational switch that positions the C-terminal that the subsequent slower fall in ErbB1-pY levels involves reloc-alization of receptors to phosphatase-rich intracellular compart-ments, and attenuation of signaling via endocytic degradationcytoplasmic tail of one receptor near the activation loop of the other, thereby facilitating phosphorylation in trans (Zhang et al., and the action of transcriptional feedback loops (Avraham and Yarden, 2011). However, several experiments suggest a moredynamic and antagonized by potent phosphatases. We develop a kinetic scheme for binding of anti-ErbB1 drugs to receptors and show that rapid phospho-turnover significantly impacts their mecha-nisms of action