Endosomes

Following activation, receptors such as those for growth factors are internalised into endosomes, in a process that was originally considered to be exclusively a recycling process. However, more recent studies have demonstrated that endosomes also act as signalling platforms, allowing propagation of MAPK cascades (Hancock 2003).

Signalling components, including Shc, Grb2, SOS and Ras, have been found on endosomes containing EGFR (Pol et al. 1998). After receptor internalisation, EGF does not dissociate from the EGFR (Lai et al. 1989), which remains tyrosine phosphorylated and co-localises with GTP-Ras (Burke et al. 2001; Jiang and Sorkin 2002). Cells deficient in clathrin-mediated endocytosis also exhibit impaired activation of ERK by various receptor tyrosine kinases (Vieira et al. 1996; Kranenburg et al. 1999), suggesting endocytosis is an important step in MAPK signalling.

Interestingly, signalling from H-Ras, but not K-Ras, is dependant on efficient endo-cytosis (Roy et al. 2002), highlighting again the functional differences between the Ras isoforms. Showing that activation of MAPK components can occur from endo-somes, and not from membrane-associated receptors prior to endocytosis, is a difficult proposition. However, an elegant study from Wang et al. (2002) demonstrated that internalised EGFR, contained in endosomes, can activate ERK.

Signalling from endosomes may provide specificity of MAPK signalling and therefore modulate cellular responses. For neuronal cells in particular, endosomes appear to provide an important platform for MAPK components in response to growth factors. These cells must interpret stimuli from multiple neurotrophins that bind to receptors at synaptic terminals (Chao 2003). The signals have to be transported along the length of axons and dendrites, some up to 1 m long, to the cell body and the nucleus. Compelling evidence suggests that endosomes provide the cells with the solution to this problem. Following NGF binding, phosphorylated TrkA receptors are found in vesicles that also contain Shc, Ras, C-Raf and ERK (Howe et al. 2001). These endosomes are transported by retrograde motion into the cell body (Howe and Mobley 2004), and accumulation of phosphorylated TrkA receptors can be found in the cell bodies of neurons (Howe and Mobley 2005). Analysis in PC 12 cells implies that MAPK signalling from endosomes and the plasma membrane can differentially regulate cellular responses to stimuli. Following NGF stimulation, active TrkA receptors, contained within endosomes, are able to promote both neuronal survival and differentiation, while active TrkA receptors confined to the plasma membrane can promote only cell survival (Zhang et al. 2000).

As described above, NGF induces internalisation and retrograde transport of the TrkA receptor in neurons. However, another neurotrophin that also signals through the TrkA receptor, NT-3, does not cause internalisation (Kuruvilla et al. 2004). These two neurotrophins play divergent roles, at different times, during development of the nervous system (reviewed in Chao 2003). Therefore, these two factors provide an example of how compartment-specific signalling can produce distinct responses from the same receptor.

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