Figure 11. ET-1 signals in SMCs through p66Shc.

Schematic of proposed regulation of cellular contraction by p66Shc. (A) In quiescent cells with unoccupied endothelin receptors (ETR), p66Shc is not phosphorylated and restrains activity of TRPC channel. (B) Activation of ET-1 signaling cascade results in Ser36 phosphorylation and intracellular relocation of p66Shc accompanied by activation of TRPC channels. (C) In cells expressing p66Shc with mutated phosphorylation site, the negative regulation of TRPC channels by p66Shc prevails and contraction remains low. ET-1 is unable to disable inhibitory activity of p66Shc. (D) In cells deficient in p66Shc, activation of TRPC channels by ET-1 is dramatically increased due to the absence of the restraining activity of p66Shc.