Expert Reviews in Molecular Medicine: http://www.expertreviews.org/
Accession information: (02)00444-1h.htm (shortcode: swf001wkg); 14 August 2002
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Animation of the organisation and function of the Ras–Raf–MEK–ERK pathway

Walter Kolch, Ashwin Kotwaliwale, Keith Vass and Petra Janosch

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Shockwave Flash 5.0 file (swf001wkg).
This animation will play continuously but you will need the latest version of the Macromedia Shockwave Flash Player on your Netscape 3.0+ (or Internet Explorer 3.0+) browser.
Stop and Play buttons: are at the bottom of the animation, click on them at any time.
Green timeline: shows how far the animation has progressed (it is not possible to slide this across).
Arrows: time points - if you click on these, the animation will play from this point.
If you are using a PC with a right-hand mouse button: click on the animation area and use to 'zoom in and out' and rewind or go back a frame etc.

Movie 1 (HTML version only). The organisation and function of the Ras–Raf–MEK–ERK pathway. This animation was created in collaboration with the authors by the editorial team of Expert Reviews in Molecular Medicine, and is based on the model presented in Figure 2 (fig002wkg). It summarises the current consensus of the organisation and function of the Ras–Raf–MEK–ERK pathway using epidermal growth factor (EGF) as a paradigm. The binding of EGF induces receptor dimerisation and autophosphorylation (P) on tyrosine residues. These phosphotyrosines function as docking sites for signalling molecules including the Grb2–SOS complex, which activates the small G-protein Ras by stimulating the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). This exchange elicits a conformational change in Ras, enabling it to bind to Raf-1 and recruit it from the cytosol to the cell membrane, where Raf-1 activation takes place. Raf-1 activation is a multi-step process that involves the dephosphorylation of inhibitory sites by protein phosphatase 2A (PP2A) as well as the phosphorylation of activating sites by PAK (p21^rac/cdc42-activated kinase), Src-family and yet unknown kinases. Activated Raf-1 phosphorylates and activates MEK (MAPK/ERK kinase), which in turn phosphorylates and activates extracellular-signal-regulated kinase (ERK). The interaction between Raf-1 and MEK can be disrupted by RKIP (Raf kinase inhibitor protein; not shown). The whole three-tiered kinase cascade is scaffolded by KSR (kinase suppressor of Ras). Activated ERK has many substrates in the cytosol [e.g. cytoskeletal proteins, phospholipase A2, and signalling proteins including tyrosine kinase receptors, oestrogen receptors, SOS, signal transducer and activator of transcription proteins (STATs) and others (Refs 10, 11)]. ERK can also enter the nucleus to control gene expression by phosphorylating transcription factors such as Elk-1 and other Ets-family proteins. Grb2, growth-factor-receptor-binding protein 2; SOS, ‘son of sevenless’; SRF, serum response factor (swf001wkg).

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