Disease relevance of Shc

• Transformation by polyoma virus middle T-antigen involves the binding and tyrosine phosphorylation of Shc [1].

High impact information on Shc

• The Drosophila SHC adaptor protein is required for signaling by a subset of receptor tyrosine kinases [2].
• A point mutation in the phosphotyrosine binding (PTB) domain completely abolishes DSHC function and provides in vivo evidence for the function of PTB domains [2].
• The in vitro selectivity of the dNumb PTB domain is therefore markedly different from those of the Shc and IRS-1 PTB domains, in that it interacts preferentially with a GP(p)Y motif, rather than NPXpY, and does not absolutely require ligand phosphorylation for binding [3].
• The Shc adaptor protein, hereafter referred to as ShcA, possesses two distinct phosphotyrosine-recognition modules, a C-terminal Src homology 2 (SH2) domain and an N-terminal phosphotyrosine-binding (PTB) domain, and is itself phosphorylated on tyrosine in response to many extracellular signals [4].
• We found that the Numb PTB domain but not the Shc PTB domain interacts with Nak through a peptide of 11 amino acids, implicating a novel and specific protein-protein interaction [5].

Biological context of Shc

• Numb has a protein domain homologous to the phosphotyrosine-binding domain (PTB) in the adaptor protein Shc [6].
• The 45-kDa dShc protein is closely related both in overall organization and in amino acid sequence (46% identity) to the 52-kDa mammalian Shc isoform [7].
• Shc itself contains an SH2 domain at its carboxyl terminus, but the function of the amino-terminal half of the protein is unknown [8].
• We show that mutant Dos proteins lacking the putative binding sites for the SH2 domains of Shc, PhospholipaseC-gamma (PLC-gamma) and the regulatory subunit of Phosphoinositide 3-kinase (PI3-K) can substitute the loss of endogenous Dos function during development [9].
• The dshc gene, which maps to position 67B-C on the third chromosome, encodes a 45-kDa protein that is widely expressed throughout the Drosophila life cycle [7].

Associations of Shc with chemical compounds

• In Shc, this domain interacts with specific phosphotyrosine containing motifs on receptor tyrosine kinases and other signaling molecules [6].
• Characterization of the phosphotyrosine-binding domain of the Drosophila Shc protein [10].
• The Shc amino-terminal domain also bound to the autophosphorylated nerve growth factor receptor (Trk), but bound significantly less well to a mutant receptor in which tyrosine Y490 in the receptor's Shc-binding site had been substituted by phenylalanine [8].

Physical interactions of Shc

• Two independent amino acid changes that interfere with Shc binding to phosphotyrosine residues do not affect Numb activity in vivo [6].

Analytical, diagnostic and therapeutic context of Shc

• Several amino acid residues in Shc have been implicated by site-directed mutagenesis to be critical for Shc binding to receptor tyrosine kinases [6].

References