RAS Pathway v2.0

January 13, 2015, by Frank McCormick

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Many thanks for your valuable input into the RAS pathway diagram.  Gaddy Getz and Matt Myerson and colleagues at the Broad Institute along with Bob Stephens, Jim Hartley and colleagues at the Frederick National Laboratory for Cancer Research are utilizing this diagram to develop a RAS-centric version of The Cancer Genome Atlas (TCGA). We hope that this will provide useful data for the RAS community to investigate as well as reveal new and provocative functional relationships.

Our original pathway diagram (posted on October 22, 2014) has been altered incorporating suggestions from the following investigators:

• Phil Stork (stork@ohsu.edu) suggested adding RASGRP1, but but we left out PDZGEF1 which (I think) is a RAP1  GEF, not a RAS GEF.  Any input on this would be welcome.
• Julie Irving (julie.irving@ncl.ac.uk) suggested adding FLT3 (also suggested by Kevin Shannon shannonk@peds.ucsf.edu), PTPN11 (also suggested by Ben Braun, UC San Francisco) and CBL. On Ben’s advice, PTPN11 was kept vague with a positive arrow to RAS activation of RAF, without a clear target.
• Manuela Baccarini (manuela.baccarini@univie.ac.at) noted  that MAP2K1 activates PTEN by sending it to the plasma membrane. RAF1 inhibits ROCK2, but was not included  in our updated diagram because the drawing was getting too complicated. This may be fixed in a subsequent version.
• Mike Nickerson (nickersonml@mail.nih.gov) included negative feedback to IRS1 and 2 from the PI3 kinase pathway.
• Anne Goriely (anne.goriely@imm.ox.ac.uk) suggested adding the MRAS (RRAS3) –SHOC2.PPP1CA pathways that activate RAF kinase and ERF, an ETS-family protein that inhibits ERK1 (aka MAPK3) and 2 (MAPK1).
• Eric Collisson (eric.collison@ucsf.edu) suggested adding the RHO GEF ARHGEF2, aka GEF-H1. Rob Rottopel has recently shown this also acts on the MAPK pathway via interaction with KSR1, but I couldn’t find a way of representing that in this version.
• Jim DeCaprio (james_decaprio@dfci.harvard.edu) suggested adding cyclin D2 (CCND2) and 3 (CCND3) in addition to Cyclin D1 (CCND1) as MAPK targets.
  Ping Lu (klu@bidmc.harvard.edu) suggested adding PIN1 as an activator of RAF1 kinase (aka CRAF). It could have been added at many other sites (see Cell Res 24, 1033, 2014 for a review by Zhimin Lu and Tony Hunter).
• Michael Tainsky (mat@wayne.edu) noted that AP2 is essential for RAS transformation, but I couldn't find a direct link to the RAS pathway.  Any suggestions are welcome.
• Maria Zajac-Kaye (mzajackaye@ufl.edu) suggested adding E2F target genes, including thymidilate synthase (TYMS).  Target genes that appear on other parts of the pathway were not listed, to keep it simple.
• Ramon Parsons (ramon.parsons@mssm.edu) suggested adding the RAC GEF, PREX2.
• Shyam Biswal (sbiswal@jhu.edu) and Carola Neumann (neumannc@upmc.edu) suggested adding NFE2L2 (aka NRF2), and NOX1.
• Eric O’Neill (eric.oneill@oncology.ox.ac.uk) suggested adding a mini-version of the Hippo pathway (RASSF, MST [STK3 and 4], SAV1, YAP1).
• Joe Ramos (joeramos@hawaii.edu) and Naoto Ueno (nueno@mdanderson.org) suggested adding PEA15.
• Larry Feig (larry.feig@tufts.edu) suggested adding RASGRF1 and 2.
• Howard Crawford (crawford.howard@mayo.edu) proposed adding VAV1, ECT2 and TIAM1. Howard also suggested DOCK10, but I wasn’t sure where to put it. Suggestions welcome!
• Mike White (michael.white@utsouthwestern.edu) suggested adding EXOC1-8 connected to the RALA, B node and CNKSR1, CNKSR2, SHOC2 connected to the RAF node.
• Karen Cichowski (kcichowski@rics.bwh.harvard.edu)  suggested adding DAB21P and INPP4B.
• Andrew Sharrocks (a.d.sharrocks@manchester.ac.uk) suggested adding ELK1.
• Mark Philips (philim01@nyu.edu) suggested adding FNTA and B, RCE1 and ICMT1.
• Debbie Morrison (morrisod@mail.nih.gov) suggested adding a feedback arrow from MAPK1,3 to the RAFs.
• Channing Der (cjder@med.unc.edu) suggested adding MYC as a MAPK1/3 substrate. He also included RGL, RGL2 and RGL3 with RALGDS as another effector that links RAS with RAL. Additionally, the RALGAPs, RALGAPA1 and RALGAPA2, and PLCE1 are included as  RAS effectors.
• Philippe Roux (philippe.roux@umontreal.ca) pointed out errors in the pathway as originally drawn: “The pathway should indicate that RPS6KB1 and RPS6KB2 are targets of mTOR (they are the p70 S6Ks). The related p90 S6Ks (RPS6KA1, RPS6KA2, RPS6KA3, RPS6KA6) are actually targets of MAPK1/3, and should be transferred to that branch of the pathway."  Steen Hansen (steen.hansen@childrens.harvard.edu) also pointed out these errors and suggested we add FOSL1 downstream of RPS6KA1,2,3 and 6. Additionally, there are two more isoforms of EIF4EBPs, and thus the pathway should indicate EIF4EBP1-3.
• Julian Downward (julian.downward@cancer.org.uk) also noted some errors, “You should have PIK3CA, PIK3CD and PIK3CG here, but not PIK3CB as p110beta does not interact with RAS. Also, for regulatory subunits, there should be PIK3R 1, 2, 3, 5, and 6, but not 4 – this is VPS15, the regulatory partner of VPS34. PIK3R 5 and 6 are the regulatory subunits of p110gamma, so are fine to have here.”  

Thank you for these suggestions.

Gene Names, Cognate Proteins, and Aliases in the RAS Pathway

The table comprises the name of each human gene in the RAS Pathway diagram,  the name of the cognate protein for each gene, and gene aliases (alternative names).  The aliases in bold are gene names more commonly used by RAS researchers. Gene names, protein names, and gene aliases were obtained from BioGPS.

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