Signal Transduction through Tyrosine‐Phosphorylated Carboxy‐Terminal Fragments of APP via an Enhanced Interaction with Shc/Grb2 Adaptor Proteins in Reactive Astrocytes of Alzheimer's Disease Brain

Abstract

The processing of the amyloid precursor protein (APP) through the formation of C-terminal fragments (CTFs) and the production of beta-amyloid, are events likely to influence the development and the progression of Alzheimer's disease (AD). APP is a transmembrane protein similar to a cell-surface receptor with the intraluminal NPTY motif in the cytosolic C terminus. Although APP holoprotein can be bound to intracellular proteins like Fe65, X11, and mDab, the ultimate function and the mechanisms through which this putative receptor transfers its message are unclear. Here it is shown that in human brain, a subset of tyrosine-phosphorylated CTFs represent docking sites for the adaptor protein ShcA. ShcA immunoreactivity is greatly enhanced in Alzheimer's patients; it is mainly localized to glial cells and occurs at reactive astrocytes surrounding cerebral vessels and amyloid plaques. Grb2 also is involved in complexes with ShcA and tyrosine-phosphorylated CTFs, and in AD brain the interaction between Grb2-ShcA and CTFs is enhanced. Also, a higher amount of phospho-ERK1,2 is present in AD brain in comparison with control cases, likely as a result of the ShcA activation. In vitro experiments show that the ShcA-CTFs interaction is strictly confined to glial cells when treated with thrombin, which is a well-known ShcA and ERK1,2 activator, mitogen, and regulator of APP cleavage. In untreated cells ShcA does not interact with either APP or CTFs, although they are normally produced. Altogether these data suggest that CTFs are implicated in cell signaling via Shc transduction machinery, likely influencing MAPK activity and glial reaction in AD patients.

Amyloid Precursor Protein Is a Primary Androgen Target Gene That Promotes Prostate Cancer Growth

“…The Kunitz protease inhibitor domain is contained in the nonneuronal isoforms including APP-770, APP-751, and APP-733, but not the neural isoform APP-695. The cytoplasmic tail of APP is also shown to bind to cytoplasmic proteins such as FE65 and Shc (15,16). APP modulates cell motility and cell adhesion by interacting with the actin cytoskeleton, integrins, and extracellular matrix (17,18).…”

Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-β–degrading Enzyme Neprilysin

“…Possibly, it might involve changes in phosphorylation of AICD and the interaction with its binding partners. The C-terminus of APP contains a consensus motif (682YENPTY687) that interacts with the phosphotyrosine binding (PTB) domains of several cytoplasmic adaptor proteins, including Fe65, X11, JIP1-B, JIP2, mDab1, Numb and ShcA (Borg et al, 1996;Howell et al, 1999;Roncarati et al, 2002;Russo et al, 2002;Scheinfeld et al, 2002;Tarr et al, 2002b). Phosphorylation of AICD at T668 influences AICD stability and leads to destabilization of AICD during differentiation of primary neurons in culture (Kimberly et al, 2005).…”

The DISC locus in psychiatric illness

“…196 Grb2 may also be involved in the pathology of Alzheimer's Disease through binding the amyloid precursor protein (APP) 197 and APP-processed fragments. 198,199 This latter interaction is detectable in human brain and is upregulated in postmortem brain tissue from Alzheimer's Disease cases. 200 Interestingly, Grb2 also binds presenilin 1 (PS1), which is involved in cleavage of APP.…”