A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity.
Ras family GTPases (RFGs) are known to share many regulatory and effector proteins. How signaling and biological specificity is achieved is poorly understood. Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site of Raf proteins bound to other molecules of M-Ras or Ras. Therefore, distinct RFGs, through independent effectors, can regulate different steps in the activation of Raf kinases. Shoc2 function is essential for activation of the MAPK pathway by growth factors. Furthermore, in tumor cells with Ras gene mutations, inhibition of Shoc2 expression inhibits MAPK, but not PI3K activity. We propose that the Shoc2-PP1c holoenzyme provides an attractive therapeutic target for inhibition of the MAPK pathway in cancer.
Rodriguez-Viciana
Pablo
P
Cancer Research Institute and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA. pviciana@cc.ucsf.edu
Oses-Prieto
Juan
J
Burlingame
Alma
A
Fried
Mike
M
McCormick
Frank
F
D015153:Blotting, Western; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D020134:Catalytic Domain; D002460:Cell Line; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000737:chemistry*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D020035:Holoenzymes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D013058:Mass Spectrometry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000737:chemistry*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D011233:Precipitin Tests; D054645:Protein Phosphatase 1; D017434:Protein Structure, Tertiary; D040901:Proteomics / Q000379:methods; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry*; D012190:Retroviridae / Q000235:genetics; D018631:ras Proteins / Q000302:isolation & purification / Q000378:metabolism*
D020035:Holoenzymes; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C112913:SHOC2 protein, human; D049452:Green Fluorescent Proteins; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D010744:Phosphoric Monoester Hydrolases; D018631:ras Proteins