Abstract
Raf-1 protects cells from apoptosis, independently of its signals to MEK and ERK, by translocating to the mitochondria where it binds Bcl-2 and displaces BAD. However, the answer to the question of how Raf-1 is normally lured to the mitochondria and becomes activated remains elusive. p21-activated protein kinases (Paks) are serine/threonine protein kinases that phosphorylate Raf-1 at Ser-338 and Ser-339. Here we elucidate the molecular mechanism through which Pak1 signals to BAD through a Raf-1-activated pathway. Upon phosphorylation by Pak1, Raf-1 translocates to mitochondria and phosphorylates BAD at Ser-112. Moreover, the mitochondrial translocation of Raf-1 and the interaction between Raf-1 and Bcl-2 are regulated by Raf-1 phosphorylation at Ser-338/Ser-339. Notably, we show that formation of a Raf-1-Bcl-2 complex coincides with loss of an interaction between Bcl-2 and BAD. These signals are specific for Pak1, because Src-activated Raf-1 only stimulates the MAP kinase cascade. Thus, our data identify the molecular connections of a Pak1-Raf-1-BAD pathway that is involved in cell survival signaling.
Highlights
Apoptotic stimuli are divided into two broad categories, extrinsic and intrinsic
Plasma membrane targeting of Raf-1 activates the classical MEK1/ERK (MAPK) cascade but does not protect cells, whereas mitochondrial targeting of Raf-1 protects cells from apoptosis [12]
Pak1 Induces Raf-1 Translocation to the Mitochondria—As targeting active Raf-1 to the mitochondria is necessary for cell protection and the phosphorylation of BAD, we tested to determine if Pak1 phosphorylation of Raf-1 stimulates its translocation to mitochondria
Summary
Apoptotic stimuli are divided into two broad categories, extrinsic and intrinsic. Extrinsic signals are receptor-mediated and are independent of the mitochondria. The MEK-independent signal is not well defined, with conflicting studies on the role of Raf-1 in BAD phosphorylation [12, 14, 15]. Another group of kinases that can protect cells from intrinsic stimuli but are not as well studied is the Pak family (p21activated kinase) [16]. Pak protein kinases were found based on their ability to bind the small GTPases Rac and Cdc42 [17] These kinases promote cell motility [18], transformation [19, 20], and cell survival [21,22,23]. Pak stimulates Raf-1 translocation to the mitochondria, stimulates complexes between
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
