| 背景 | Raf-1 (also C-Raf) is a ubiquitously expressed, 73 kDa, 648 amino acid (aa) Raf subfamily, Ser/Thr protein kinase family enzyme. Raf-1 is an entry point into the MAP kinase/Erk-1/2 signaling pathway. The molecule contains three distinct regions; an N-terminal RBD (Ras-binding domain) (amino acids 56-131), followed by two rich segments [a cysteine-finger region (amino acids 138-184) (also called CR1/C1) and a second cysteine-rich region (CR2) (amino acids 253-264)] and a C-terminal Ser/Thr kinase catalytic domain (amino acids 354-611). In general, Raf-1 phosphorylates and activates MEK-1/2. MEK-1/2, in turn, phosphorylates and activates
ERK-1/2. The activation of Raf-1 begins upstream at the plasma membrane with the activation of Ras. During Ras activation, Raf-1 is inactive, in part because a
14-3-3 protein constitutively binds to phosphorylated Ser 259 and Ser 621 residues on Raf-1. Once activated, Ras binds Raf-1 on the Raf RBD, and displaces 14-3-3, allowing for additional Ras binding to the CR1. These two ligations now activate Raf-1. In the inactive state, Raf-1 is constitutively phosphorylated on Ser 43, Ser 259, and Ser 621. Upon activation, Ser 338, Tyr 431, Tyr 491, and Ser 494 also become phosphorylated, with phosphorylation at Ser 338 inducing activation. Down-regulation of Raf-1 occurs on other sites. Phosphorylation on proline-directed serine sites at position 301 and 642 are posited to be part of a negative feedback system regulated by ERK. |
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