An Alternative to SH2 Domains for Binding Tyrosine-Phosphorylated Proteins

Kavanaugh, W M; Williams, L T

doi:10.1126/science.7527937

Cited by 496 publications

(357 citation statements)

References 15 publications

Supporting

Mentioning

348

Contrasting

Unclassified

Order By: Relevance

“…dDab and Dab2 contain a phosphotyrosine interaction domain (PID, or PTB) domain within the N-terminal 140 amino acids (Bork and Margolis, 1995). Similar to SH2 domains, the PID domain of Shc and other proteins has been shown to bind phosphotyrosine residues within the context of speci®c amino acid sequences (Kavanaugh and Williams, 1994;Blaikie et al, 1994;Pawson, 1994). Dab2 also contains a C-terminal proline-rich domain, the sequence of which resembles the proline-rich motifs contained in Sos (Bowtell et al, 1992;Chardin et al, 1993), a guanine nucleotide exchange factor for Ras (Scheme I).…”

Section: Introductionmentioning

confidence: 99%

Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2

et al. 1998

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2

et al. 1998

View full text Add to dashboard Cite

“…The phosphotyrosine (pTyr)-binding (PTB) domain (also referred to as the PI domain) was originally identi®ed in the Shc and IRS-1 docking proteins, through its ability to recognize speci®c pTyr-containing sites on activated receptor protein tyrosine kinases (Blaikie et al, 1994;Kavanaugh and Williams, 1994;O'Neill et al, 1994;van der Geer et al, 1995). These PTB domains are functionally similar to SH2 domains in the sense that they bind directly to short peptide motifs in a fashion that is regulated by phosphorylation of the ligand, and depends on residues¯anking the phosphorylation site (Songyang et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site

1999

View full text Add to dashboard Cite

Shc and IRS-1 (and their relatives) are cytoplasmic docking proteins that possess phosphotyrosine-binding (PTB) domains, through which they bind speci®c activated receptor tyrosine kinases (RTK). The subsequent phosphorylation of Shc or IRS-1 creates binding sites for the SH2 domains of multiple signaling proteins, leading to the activation of intracellular biochemical pathways. The PTB domains of Shc and IRS-1 both recognize autophosphorylation sites in RTKs with the consensus sequence NPXpY, but show distinct abilities to bind stably to RTKs such as the TrkA nerve growth factor receptor and the insulin receptor. In vitro analysis has suggested that residues N-terminal to the NPXpY motif may determine the a nity with which phosphopeptide ligands are recognized by the Shc and IRS-1 PTB domains. Unlike IRS-1, the Shc PTB domain binds poorly to the insulin-receptor (IR) b subunit in vitro, owing to its low a nity for the NPXpY autophosphorylation site at Tyr 960 of the IR. As a consequence, Shc does not bind stably to the activated IR in cells. We show that substitution of Ser 955, ®ve residues Nterminal to the Tyr 960 autophosphorylation site (the 75 position), with Ile alters the target speci®city of the IR such that it stably associates with Shc in insulinstimulated cells. A triple substitution of the 75, 78 and 79 residues relative to Tyr 960 of the IR to the corresponding amino acids found in the Shc PTB domain binding site of TrkA results in even stronger binding of the IR to Shc in vivo. The variant IRs with enhanced ability to bind Shc showed an increased ability to activate the MAPK pathway in response to insulin stimulation. These results demonstrate that subtle di erences in residues N-terminal to NPXpY autophosphorylation sites determine the ability of RTKs to bind speci®c PTB domain proteins in vivo, and thus modify the signaling properties of activated receptors.

show abstract

“…The adaptor protein Shc is an early mediator of this process (Rozakis-Adcock et al, 1992). Shc contains an N-terminal phosphotyrosine binding motif (PTB), a central collagen homology domain (CH) where the primary site of tyrosine phosphorylation (Y317) resides, and a C-terminal SH2 domain (Kavanaugh and Williams, 1994;Pelicci et al, 1992). After autophosphorylation of receptors, Shc is recruited to the receptor via phosphotyrosine binding motifs (Rozakis-Adcock et al, 1992;Egan et al, 1993).…”

Section: Introductionmentioning

confidence: 99%