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Abstract:
Protein-protein interactions govern cellular functions on the molecular level.
Post-translational modifications alter these interactions allowing highly dynamic
regulation. Protein tyrosine phosphorylation is an especially relevant post-trans-
lational modification, because it is tightly linked to intercellular regulation of
growth and development in metazoans. Diseases like cancer or autoimmune
disorders arise from misregulation of these processes generating great medical
interest in protein tyrosine phosphorylation and processes relating to it. This
study provides a comprehensive set of 292 mostly novel, high-quality phospho-
tyrosine-dependent protein-protein interactions detected in genome-scale yeast
two-hybrid screens using full-length proteins filling a gap in phosphotyrosine
signaling knowledge, which has so far been based largely on peptide binding and
affinity purification-coupled mass spectrometry experiments. The high quality
was demonstrated experimentally and computationally, in co-immunoprecip-
itation and protein complementation assays, as well as over-representation
analyses and comparison to prior knowledge. Previously reported linear peptide
motifs are reflected in the binding partners, but clearly do not account for most
of the interactions, emphasizing the relevance of full-length protein context.
The interactions were further shown to form an unusually dense, monolithic
network with a central core and reflect and expand phosphotyrosine-related
KEGG pathways. Seven of the eight core proteins are well-established signaling
hubs. The eighth core gene, SH2D2A, seems to play a more central role than
currently appreciated. Finally, selected interactions involving GRB2 were shown
to occur in different specific subcellular localizations. Together, these results
strongly suggest that the interactions presented here represent an important
step toward understanding growth and development and will benefit treatment
of pressing medical issues substantially.
