Growth factor receptor-bound protein 2 interaction with the tyrosine-phosphorylated tail of amyloid beta precursor protein is mediated by its src homology 2 domain.

The sequential processing of the familial disease gene product amyloid ? precursor protein (A?PP) by ?- and ?-secretases generates amyloid ?, which is considered to be the pathogenic factor of Alzheimer's disease, and the AID peptide (A?PP intracellular domain). The AID peptide acts as a positive regulator of apoptosis and modulates transcription and calcium release. To gain clues about the molecular mechanisms regulating the function of A?PP and AID, proteins interacting with the AID region of A?PP have been isolated using the yeast two-hybrid system. Recent evidence indicates that A?PP undergoes post-translational modification events in the AID region and that phosphorylation might regulate its affinity for interacting proteins. To test this possibility and to uncover A?PP-binding partners whose interaction depends on A?PP phosphorylation, we used a proteomic approach. Here we describe a protein, growth factor receptor-bound protein 2 (Grb2), that specifically binds A?PP, phosphorylated in Tyr682. Furthermore, we show that this interaction is direct and that Grb2 binds to phospho-A?PP via its Src homology 2 region. Together with the evidence that Grb2 is in complex with A?PP in human brains and that these complexes are augmented in brains from Alzheimer's cases, our data indicate that Grb2 may mediate some biological and possibly pathological A?PP-AID function.