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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.

References

Andreev, J., Galisteo, M.L., Kranenburg, O., Logan, S.K., Chiu, E.S., Okigaki, M., Cary, L.A., Moolenaar, W.H., and Schlessinger, J. Src and Pyk2 mediate G-protein-coupled receptor activation of epidermal growth factor receptor (EGFR) but are not required for coupling to the mitogen-activated protein (MAP) kinase signaling cascade. J. Biol. Chem. 276, 20130-20135 (2001). [Abstract] [Full Text]

Andresen, B.T., Rizzo, M.A., Shome, K., and Romero, G. The role of phosphatidic acid in the regulation of the Ras/MEK/Erk signaling cascade. FEBS Lett. 531, 65-68 (2002).

Carroll, M.P. and May, W.S. Protein kinase C-mediated serine phosphorylation directly activates Raf- 1 in murine hematopoietic cells. J. Biol. Chem. 269, 1249-1256 (1994). [Abstract]

Daaka, Y., Luttrell, L.M., Ahn, S., Della Rocca, G.J., Ferguson, S.S., Caron, M.G., and Lefkowitz, R.J. Essential role for G protein-coupled receptor endocytosis in the activation of mitogen-activated protein kinase. J. Biol. Chem. 273, 685-688 (1998). [Abstract] [Full Text]

Escano, C.S., Jr., Keever, L.B., Gutweiler, A.A., and Andresen, B.T. Angiotensin II activates extracellular signal-regulated kinase independently of receptor tyrosine kinases in renal smooth muscle cells: implications for blood pressure regulation. J. Pharmacol. Exp. Ther. 324, 34-42 (2008). [Abstract] [Full Text]

Kim, I.M., Tilley, D.G., Chen, J., Salazar, N.C., Whalen, E.J., Violin, J.D., and Rockman, H.A. {beta}-Blockers alprenolol and carvedilol stimulate {beta}-arrestin-mediated EGFR transactivation. Proc . Natl. Acad. Sci. U. S. A. 105, 14555-14560 (2008). [Abstract] [Full Text]

Luttrell, L.M., Roudabush, F.L., Choy, E.W., Miller, W.E., Field, M.E., Pierce, K.L., and Lefkowitz, R.J. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc . Natl. Acad. Sci. U. S. A. 98, 2449-2454 (2001). [Abstract] [Full Text]

Mason, C.S., Springer, C.J., Cooper, R.G., Superti-Furga, G., Marshall, C.J., and Marais, R. Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J. 18, 2137-2148 (1999). [Abstract] [Full Text]

Rakesh, K., Yoo, B., Kim, I.M., Salazar, N., Kim, K.S., and Rockman, H.A. β-Arrestin-biased agonism of the angiotensin receptor induced by mechanical stress. Sci. Signal. 3, ra46 (2010). [Abstract] [Full Text]

Rizzo, M.A., Shome, K., Vasudevan, C., Stolz, D.B., Sung, T.C., Frohman, M.A., Watkins, S.C., and Romero, G. Phospholipase D and its product, phosphatidic acid, mediate agonist- dependent raf-1 translocation to the plasma membrane and the activation of the mitogen-activated protein kinase pathway. J. Biol. Chem. 274, 1131-1139 (1999). [Abstract] [Full Text]

Schonwasser, D.C., Marais, R.M., Marshall, C.J., and Parker, P.J. Activation of the mitogen-activated protein kinase/extracellular signal- regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol. Cell Biol. 18, 790-798 (1998). [Abstract] [Full Text]

Tapinos, N. and Rambukkana, A., 2005. Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli. Proc. Natl. Acad. Sci. U. S. A. 102, 9188-9193. [Abstract] [Full Text]

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