Abstract
Mitogen-activated protein kinase (MAPK) pathways form the backbone of signal transduction in the mammalian cell. Here we applied a systematic experimental and computational approach to map 2,269 interactions between human MAPK-related proteins and other cellular machinery and to assemble these data into functional modules. Multiple lines of evidence including conservation with yeast supported a core network of 641 interactions. Using small interfering RNA knockdowns, we observed that approximately one-third of MAPK-interacting proteins modulated MAPK-mediated signaling. We uncovered the Na-H exchanger NHE1 as a potential MAPK scaffold, found links between HSP90 chaperones and MAPK pathways and identified MUC12 as the human analog to the yeast signaling mucin Msb2. This study makes available a large resource of MAPK interactions and clone libraries, and it illustrates a methodology for probing signaling networks based on functional refinement of experimentally derived protein-interaction maps.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Base Sequence
-
Cation Transport Proteins / genetics
-
Cation Transport Proteins / metabolism
-
Cell Line
-
Cell Membrane / metabolism
-
Cloning, Molecular
-
DNA, Complementary / genetics
-
HSP90 Heat-Shock Proteins / genetics
-
HSP90 Heat-Shock Proteins / metabolism
-
Humans
-
Intracellular Signaling Peptides and Proteins / genetics
-
Luciferases / genetics
-
MAP Kinase Signaling System / genetics
-
MAP Kinase Signaling System / physiology*
-
Mitogen-Activated Protein Kinases / genetics
-
Mitogen-Activated Protein Kinases / metabolism*
-
Mitogen-Activated Protein Kinases / physiology
-
Molecular Sequence Data
-
Mucins / genetics
-
Mucins / metabolism
-
NF-kappa B / genetics
-
NF-kappa B / metabolism
-
Proteomics / methods*
-
RNA, Small Interfering / genetics
-
Saccharomyces cerevisiae / genetics
-
Saccharomyces cerevisiae / metabolism
-
Saccharomyces cerevisiae Proteins / genetics
-
Sodium-Hydrogen Exchanger 1
-
Sodium-Hydrogen Exchangers / genetics
-
Sodium-Hydrogen Exchangers / metabolism
-
Transcription Factor AP-1 / genetics
-
Transcription Factor AP-1 / metabolism
-
Two-Hybrid System Techniques
Substances
-
Cation Transport Proteins
-
DNA, Complementary
-
HSP90 Heat-Shock Proteins
-
Intracellular Signaling Peptides and Proteins
-
MSB2 protein, S cerevisiae
-
Mucins
-
NF-kappa B
-
RNA, Small Interfering
-
SLC9A1 protein, human
-
Saccharomyces cerevisiae Proteins
-
Sodium-Hydrogen Exchanger 1
-
Sodium-Hydrogen Exchangers
-
Transcription Factor AP-1
-
Luciferases
-
Mitogen-Activated Protein Kinases