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Open Forum on Cell Signaling

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No role for RTK in GPCR activation of the Ras-MAPK pathway?

30 June 2010

Bradley T. Andresen

I do agree with Dr. Carraway. However, I have previously published results showing that in thoracic aortic smooth muscle cells (TASMCs) and renal microvascular smooth muscle cells (RμVSMCs) from Wistar-Kyoto rats, angiotensin II in TASMCs, but not RμVSMCs, requires RTK kinase activity to signal to ERK (Escano, Jr. et al., 2008). Thus, I am not surprised by the results since there are alternate pathways for GPCR-mediated activation of ERK independent of RTKs in some cell types. It is likely that the knockouts are "rewired" during development to utilize these alternative pathways, whereas the wild type is not. This is parallel to Dr. Carraway's argument.

Dr. Lockyer did ask some specific questions:

1) Does this mean that these mechanisms are less important than previously thought?

Not necessarily this has been answered previously by Dr. Carraway and in my first paragraph.

2) What are the dominant mechanisms, then, regulating GPCR-induced MAPK activation, and how might these knockout cells be bypassing these routes?

I am familiar with a few different mechanisms for GPCR activating ERK in addition to the now "canonical" transactivation pathway.

  • GPCRs may activate ERK through β-arrestin-mediated scaffolding (Daaka et al., 1998; Luttrell et al., 2001), but this has also been tied to Src and EGFR (Kim et al., 2008; Rakesh et al., 2010).
  • GPCRs may activate ERK through phospholipase D (Rizzo et al., 1999), reviewed in (Andresen et al., 2002).
  • Alternatively, GPCRs may directly activate ERK (Carroll and May, 1994; Schonwasser et al., 1998), but this pathway also utilizes Src family kinases (Mason et al., 1999; Tapinos and Rambukkana, 2005).

It may be possible for these pathways to act independently of Src and EGFR, or at least independently of Src, Yes, and Fyn, which were the only kinases examined (Andreev et al., 2001). However, one problem that has vexed me with the above theories is that there is not a solidified mechanism for GPCRs to activate Ras in these pathways. This is not true for the transactivation theory and is what makes it so appealing.


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