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Details on Person Activated Ras GTPase (RAS85D) triggers the kinase cascade wh...
| Class:Id | Summation:480994 |
|---|---|
| _displayName | Activated Ras GTPase (RAS85D) triggers the kinase cascade wh... |
| _timestamp | 2010-09-13 16:34:12 |
| created | [InstanceEdit:480995] Williams, MG, 2010-01-27 |
| modified | [InstanceEdit:500598] Williams, MG, 2010-02-04 [InstanceEdit:508453] Williams, MG, 2010-02-12 [InstanceEdit:934626] Williams, MG, 2010-08-17 [InstanceEdit:947706] Williams, MG, 2010-09-13 |
| text | Activated Ras GTPase (RAS85D) triggers the kinase cascade which characterises the Ras/Raf/ERK pathway. The Ras guanine-nucleotide exchange factor, Son of Sevenless (SOS) is involved in activating RAS85D by catalysing GTP exchange. RAS85D is subsequently downregulated when a GTPase-activating protein, GAP1 (in the Sevenless, EGFR, and PVR pathways) or vacuolar peduncle (VAP) (in the Torso and FGFR pathways), hydrolyses the bound GTP to GDP. An additional GTPase activating protein, Neurofibromin 1 (NF1), is another component involved in this cycle of events. Propagation of the signal downstream of RAS85D requires the sequential activation of the kinases: Polehole (PHL) aka Raf1, Downstream of Raf1 (DSOR1), and Rolled (RL). The former two kinases are assembled into a large complex attached to scaffold molecules: Kinase Suppressor of Ras (KSR) and Connector Enhancer of KSR (CNK). KSR additionally provides binding sites for a variety of kinases and the phosphatase PP2A, and is involved in triggering PHL activation probably through an allosteric mechanism. Initially, 14-3-3epsilon dimer proteins are bound to two phosphorylated binding sites on both PHL and KSR. This helps to mask the plasma membrane-binding C1 domains in both proteins which lie close to the binding sites, sequestering the large multi-kinase complex in the cytosol. Activated RAS85D binds to PHL in the vicinity of the plasma membrane. The protein phosphatase, PP2A, dephosphorylates one each of the 14-3-3epsilon-binding phosphorylated serine residues. The 14-3-3 dimers are now unable to bind to these residues leaving the C1 domains of PHL and KSR exposed and able to bind to the plasma membrane. Various phosphorylations and conformational changes activate PHL which in turn phosphorylates DSOR1 kinase which then phosphorylates RL kinase. In the cytosol, phosphorylated RL is involved in the activation of the Mnk1/2 orthologue, LK6 (see below). In addition, phosphorylated RL forms either a homodimer or a hemi-active dimer with an unphosphorylated RL molecule. The formed RL dimer is imported into the nucleus where it helps in the export of Anterior Open (AOP) protein, which in the absence of RL in the nucleus, polymerises and inhibits transcription. RL dimer additionally phosphorylates the protein Pointed (PNT) which then activates transcription of target genes. It is also involved in phosphorylating the components of the AP-1 transcription factor complex, Jun-related antigen (JRA):Kayak (KAY), which are also involved in the JNK signalling sub-pathway. The adaptor protein Sprouty (STY) is involved in negative regulation of the Ras/Raf/ERK pathway by inhibiting the activation of RAS85D and PHL by sequestering the SH2 containing docking protein, Downstream of receptor kinase (DRK). As SOS complexes with DRK, it will be unable to activate RAS85D. Additionally PHL can be inhibited by binding to STY, while GAP1, which can also bind to STY, inhibits RAS85D. STY itself is regulated by phosphorylation (SRC42A and LK6 kinases) and dephosphorylation (Corkscrew (CSW) and PP2A phosphatases) of key serine and tyrosine residues which can lead to its degradation by the E3 ubiquitin ligase, CBL. The sty gene is a target gene of the pathway meaning STY is involved in a negative feedback loop. The heat shock proteins HSP83 and CDC37 form a complex which then appears to bind to activated PHL but how this contributes to the current pathway model is unclear. Likewise, the PP2C protein phosphatase, alphabet (ALPH) has been identified as a negative regulator of the pathway. However, its substrate is currently unknown. |
| (summation) | [Pathway:480998] Ras/Raf/ERK pathway - not reviewed [Drosophila melanogaster] |
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