The PTB domain of ShcA couples receptor activation to the cytoskeletal regulator IQGAP1.
Adaptor proteins respond to stimuli and recruit downstream complexes using interactions conferred by associated protein domains and linear motifs. The ShcA adaptor contains two phosphotyrosine recognition modules responsible for binding activated receptors, resulting in the subsequent recruitment of Grb2 and activation of Ras/MAPK. However, there is evidence that Grb2-independent signalling from ShcA has an important role in development. Using mass spectrometry, we identified the multidomain scaffold IQGAP1 as a ShcA-interacting protein. IQGAP1 and ShcA co-precipitate and are co-recruited to membrane ruffles induced by activated receptors of the ErbB family, and a reduction in ShcA protein levels inhibits the formation of lamellipodia. We used NMR to characterize a direct, non-canonical ShcA PTB domain interaction with a helical fragment from the IQGAP1 N-terminal region that is pTyr-independent. This interaction is mutually exclusive with binding to a more conventional PTB domain peptide ligand from PTP-PEST. ShcA-mediated recruitment of IQGAP1 may have an important role in cytoskeletal reorganization downstream of activated receptors at the cell surface.
Smith
Matthew J
MJ
Ontario Cancer Institute, MaRS TMDT, Toronto, Canada.
Hardy
W Rod
WR
Li
Guang-Yao
GY
Goudreault
Marilyn
M
Hersch
Steven
S
Metalnikov
Pavel
P
Starostine
Andrei
A
Pawson
Tony
T
Ikura
Mitsuhiko
M
D000818:Animals; D002151:Calorimetry; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*
C101203:IQ motif containing GTPase activating protein 1; D055765:Shc Signaling Adaptor Proteins; D020703:ras GTPase-Activating Proteins