Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Mol. Cell. Biol. 22 (14): 5128-5140

Copyright © 2002 by the American Society for Microbiology. All rights reserved.

H-Ras Signaling and K-Ras Signaling Are Differentially Dependent on Endocytosis

Sandrine Roy, Bruce Wyse, and John F. Hancock*

Laboratory of Experimental Oncology, Department of Pathology, University of Queensland Medical School, Brisbane 4006, Australia

Received for publication 27 December 2001. Revision received 15 February 2002. Accepted for publication 16 April 2002.

Abstract: Endocytosis is required for efficient mitogen-activated protein kinase (MAPK) activation by activated growth factor receptors. We examined if H-Ras and K-Ras proteins, which are distributed across different plasma membrane microdomains, have equal access to the endocytic compartment and whether this access is necessary for downstream signaling. Inhibition of endocytosis by dominant interfering dynamin-K44A blocked H-Ras but not K-Ras-mediated PC12 cell differentiation and selectively inhibited H-Ras- but not K-Ras-mediated Raf-1 activation in BHK cells. H-Ras- but not K-Ras-mediated Raf-1 activation was also selectively dependent on phosphoinositide 3-kinase activity. Stimulation of endocytosis and endocytic recycling by wild-type Rab5 potentiated H-Ras-mediated Raf-1 activation. In contrast, Rab5-Q79L, which stimulates endocytosis but not endocytic recycling, redistributed activated H-Ras from the plasma membrane into enlarged endosomes and inhibited H-Ras-mediated Raf-1 activation. Rab5-Q79L expression did not cause the accumulation of wild-type H-Ras in enlarged endosomes. Expression of wild-type Rab5 or Rab5-Q79L increased the specific activity of K-Ras-activated Raf-1 but did not result in any redistribution of K-Ras from the plasma membrane to endosomes. These results show that H-Ras but not K-Ras signaling though the Raf/MEK/MAPK cascade requires endocytosis and endocytic recycling. The data also suggest a mechanism for returning Raf-1 to the cytosol after plasma membrane recruitment.


* Corresponding author. Mailing address: Laboratory of Experimental Oncology, Department of Pathology, University of Queensland Medical School, Herston Road, Brisbane 4006, Australia. Phone: 61 7 3365 5288. Fax: 61 7 3365 5511. E-mail: j.hancock{at}mailbox.uq.edu.au.



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Endocytosis and Cancer.
I. Mellman and Y. Yarden (2013)
Cold Spring Harb Perspect Biol 5, a016949
   Abstract »    Full Text »    PDF »
Helminth-excreted/secreted products are recognized by multiple receptors on DCs to block the TLR response and bias Th2 polarization in a cRAF dependent pathway.
C. A. Terrazas, M. Alcantara-Hernandez, L. Bonifaz, L. I. Terrazas, and A. R. Satoskar (2013)
FASEB J 27, 4547-4560
   Abstract »    Full Text »    PDF »
A Comprehensive Survey of Ras Mutations in Cancer.
I. A. Prior, P. D. Lewis, and C. Mattos (2012)
Cancer Res. 72, 2457-2467
   Abstract »    Full Text »    PDF »
Endocytosis and Signaling: Cell Logistics Shape the Eukaryotic Cell Plan.
S. Sigismund, S. Confalonieri, A. Ciliberto, S. Polo, G. Scita, and P. P. Di Fiore (2012)
Physiol Rev 92, 273-366
   Abstract »    Full Text »    PDF »
A genome-wide RNAi screen in mouse embryonic stem cells identifies Mp1 as a key mediator of differentiation.
B. A. Westerman, A. K. Braat, N. Taub, M. Potman, J. H. A. Vissers, M. Blom, E. Verhoeven, H. Stoop, A. Gillis, A. Velds, et al. (2011)
J. Exp. Med. 208, 2675-2689
   Abstract »    Full Text »    PDF »
Differential Regulation of RasGAPs in Cancer.
T. Grewal, M. Koese, F. Tebar, and C. Enrich (2011)
Genes & Cancer 2, 288-297
   Abstract »    Full Text »    PDF »
Ras, an Actor on Many Stages: Posttranslational Modifications, Localization, and Site-Specified Events.
I. Arozarena, F. Calvo, and P. Crespo (2011)
Genes & Cancer 2, 182-194
   Abstract »    Full Text »    PDF »
Demonstration of Angiotensin II-induced Ras Activation in the trans-Golgi Network and Endoplasmic Reticulum Using Bioluminescence Resonance Energy Transfer-based Biosensors.
A. Balla, L. S. Erdelyi, E. Soltesz-Katona, T. Balla, P. Varnai, and L. Hunyady (2011)
J. Biol. Chem. 286, 5319-5327
   Abstract »    Full Text »    PDF »
A clathrin-dependent pathway leads to KRas signaling on late endosomes en route to lysosomes.
A. Lu, F. Tebar, B. Alvarez-Moya, C. Lopez-Alcala, M. Calvo, C. Enrich, N. Agell, T. Nakamura, M. Matsuda, and O. Bachs (2009)
J. Cell Biol. 184, 863-879
   Abstract »    Full Text »    PDF »
Ras Subcellular Localization Defines Extracellular Signal-Regulated Kinase 1 and 2 Substrate Specificity through Distinct Utilization of Scaffold Proteins.
B. Casar, I. Arozarena, V. Sanz-Moreno, A. Pinto, L. Agudo-Ibanez, R. Marais, R. E. Lewis, M. T. Berciano, and P. Crespo (2009)
Mol. Cell. Biol. 29, 1338-1353
   Abstract »    Full Text »    PDF »
Activation of the MAPK Module from Different Spatial Locations Generates Distinct System Outputs.
K. Inder, A. Harding, S. J. Plowman, M. R. Philips, R. G. Parton, and J. F. Hancock (2008)
Mol. Biol. Cell 19, 4776-4784
   Abstract »    Full Text »    PDF »
A Unique Platform for H-Ras Signaling Involving Clathrin-independent Endocytosis.
N. Porat-Shliom, Y. Kloog, and J. G. Donaldson (2008)
Mol. Biol. Cell 19, 765-775
   Abstract »    Full Text »    PDF »
Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes..
M. C. Tuthill, C. E. Oki, and P. S. Lorenzo (2006)
Mol. Cancer Ther. 5, 602-610
   Abstract »    Full Text »    PDF »
Distinct Utilization of Effectors and Biological Outcomes Resulting from Site-Specific Ras Activation: Ras Functions in Lipid Rafts and Golgi Complex Are Dispensable for Proliferation and Transformation.
D. Matallanas, V. Sanz-Moreno, I. Arozarena, F. Calvo, L. Agudo-Ibanez, E. Santos, M. T. Berciano, and P. Crespo (2006)
Mol. Cell. Biol. 26, 100-116
   Abstract »    Full Text »    PDF »
K-ras4B and Prenylated Proteins Lacking "Second Signals" Associate Dynamically with Cellular Membranes.
J. R. Silvius, P. Bhagatji, R. Leventis, and D. Terrone (2006)
Mol. Biol. Cell 17, 192-202
   Abstract »    Full Text »    PDF »
H-Ras Dynamically Interacts with Recycling Endosomes in CHO-K1 Cells: INVOLVEMENT OF Rab5 AND Rab11 IN THE TRAFFICKING OF H-Ras TO THIS PERICENTRIOLAR ENDOCYTIC COMPARTMENT.
G. A. Gomez and J. L. Daniotti (2005)
J. Biol. Chem. 280, 34997-35010
   Abstract »    Full Text »    PDF »
Individual Palmitoyl Residues Serve Distinct Roles in H-Ras Trafficking, Microlocalization, and Signaling.
S. Roy, S. Plowman, B. Rotblat, I. A. Prior, C. Muncke, S. Grainger, R. G. Parton, Y. I. Henis, Y. Kloog, and J. F. Hancock (2005)
Mol. Cell. Biol. 25, 6722-6733
   Abstract »    Full Text »    PDF »
Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway.
J. S. Goodwin, K. R. Drake, C. Rogers, L. Wright, J. Lippincott-Schwartz, M. R. Philips, and A. K. Kenworthy (2005)
J. Cell Biol. 170, 261-272
   Abstract »    Full Text »    PDF »
An Acylation Cycle Regulates Localization and Activity of Palmitoylated Ras Isoforms.
O. Rocks, A. Peyker, M. Kahms, P. J. Verveer, C. Koerner, M. Lumbierres, J. Kuhlmann, H. Waldmann, A. Wittinghofer, and P. I. H. Bastiaens (2005)
Science 307, 1746-1752
   Abstract »    Full Text »    PDF »
Requirement of phospholipase D1 activity in H-RasV12-induced transformation.
F. G. Buchanan, M. McReynolds, A. Couvillon, Y. Kam, V. R. Holla, R. N. DuBois, and J. H. Exton (2005)
PNAS 102, 1638-1642
   Abstract »    Full Text »    PDF »
PKC controls HGF-dependent c-Met traffic, signalling and cell migration.
S. Kermorgant, D. Zicha, and P. J. Parker (2004)
EMBO J. 23, 3721-3734
   Abstract »    Full Text »    PDF »
Human RAS Superfamily Proteins and Related GTPases.
J. Colicelli (2004)
Sci. STKE 2004, re13
   Abstract »    Full Text »    PDF »
The P34G Mutation Reduces the Transforming Activity of K-Ras and N-Ras in NIH 3T3 Cells but Not of H-Ras.
J. L. Oliva, N. Zarich, N. Martinez, R. Jorge, A. Castrillo, M. Azanedo, S. Garcia-Vargas, S. Gutierrez-Eisman, A. Juarranz, L. Bosca, et al. (2004)
J. Biol. Chem. 279, 33480-33491
   Abstract »    Full Text »    PDF »
Visualizing Ras signalling in real-time.
S. A. Walker and P. J. Lockyer (2004)
J. Cell Sci. 117, 2879-2886
   Abstract »    Full Text »    PDF »
Activation of H-Ras in the Endoplasmic Reticulum by the RasGRF Family Guanine Nucleotide Exchange Factors.
I. Arozarena, D. Matallanas, M. T. Berciano, V. Sanz-Moreno, F. Calvo, M. T. Munoz, G. Egea, M. Lafarga, and P. Crespo (2004)
Mol. Cell. Biol. 24, 1516-1530
   Abstract »    Full Text »    PDF »
Exchange Factors of the RasGRP Family Mediate Ras Activation in the Golgi.
M. J. Caloca, J. L. Zugaza, and X. R. Bustelo (2003)
J. Biol. Chem. 278, 33465-33473
   Abstract »    Full Text »    PDF »
sal1 determines the number of aleurone cell layers in maize endosperm and encodes a class E vacuolar sorting protein.
B. Shen, C. Li, Z. Min, R. B. Meeley, M. C. Tarczynski, and O.-A. Olsen (2003)
PNAS 100, 6552-6557
   Abstract »    Full Text »    PDF »
Distinct Rates of Palmitate Turnover on Membrane-bound Cellular and Oncogenic H-Ras.
T. L. Baker, H. Zheng, J. Walker, J. L. Coloff, and J. E. Buss (2003)
J. Biol. Chem. 278, 19292-19300
   Abstract »    Full Text »    PDF »
Unexpected Induction of the Human Connexin 43 Promoter by the Ras Signaling Pathway Is Mediated by a Novel Putative Promoter Sequence.
G. D. Carystinos, M. Kandouz, M. A. Alaoui-Jamali, and G. Batist (2003)
Mol. Pharmacol. 63, 821-831
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882