title: System output of the MAPK module is spatially regulated.
abstract: Signaling via the Raf/MEK/ERK (MAPK) module controls multiple cell functions including proliferation, differentiation and survival. How this single pathway can regulate such diverse cell fates is unknown. Recently, we examined system outputs of the MAPK pathway from different cellular compartments. We observed robust activation of the MAPK cascade from both the plasma membrane and the Golgi. When the MAPK module is localized to plasma membrane nanoclusters corresponding to those occupied by activated H-, N- and K-ras, ERKpp output is digital, with both low and high Raf kinase inputs processed to generate a maximal ERKpp output. In contrast, when the MAPK module is localized to the Golgi, ERKpp output is graded such that Raf kinase input corresponds to ERKpp output. These results clearly demonstrate that different cellular environments available to the MAPK module can fundamentally rewire system output, which in turn may allow this single cascade to direct different cell fate decisions.
authors.affiliation: Institute for Molecular Bioscience; University of Queensland; Brisbane Australia.
authors.forename: Kerry
authors.initials: K
authors.lastname: Inder
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
references.citation: Chemphyschem. 2003 Jul 14;4(7):748-53
references.pmid: 12901307
references.citation: Nat Cell Biol. 2002 May;4(5):343-50
references.pmid: 11988737
references.citation: Mol Biol Cell. 2008 Nov;19(11):4776-84
references.pmid: 18784252
references.citation: Mol Cell Biol. 1997 Aug;17(8):4509-16
references.pmid: 9234708
references.citation: J Cell Biol. 2003 Jan 20;160(2):165-70
references.pmid: 12527752
references.citation: Proc Natl Acad Sci U S A. 2004 May 11;101(19):7317-22
references.pmid: 15123831
references.citation: Nat Cell Biol. 2001 Apr;3(4):368-75
references.pmid: 11283610
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15500-5
references.pmid: 16223883
references.citation: Science. 2005 Mar 18;307(5716):1746-52
references.pmid: 15705808
references.citation: Arch Biochem Biophys. 2002 Aug 1;404(1):3-9
references.pmid: 12127063
references.citation: Nat Cell Biol. 2007 Aug;9(8):905-14
references.pmid: 17618274
references.citation: Oncogene. 2007 May 14;26(22):3113-21
references.pmid: 17496910
references.citation: J Biol Chem. 2002 Jan 4;277(1):272-8
references.pmid: 11689566
references.citation: Mol Cell Biol. 2008 Jul;28(13):4377-85
references.pmid: 18458061
references.citation: Curr Opin Cell Biol. 1997 Apr;9(2):174-9
references.pmid: 9069260
references.citation: EMBO J. 2008 Mar 5;27(5):727-35
references.pmid: 18273062
references.citation: Nature. 2003 Aug 7;424(6949):694-8
references.pmid: 12845332