Amyloid precursor protein and amyloid precursor-like protein 2 in cancer

Abstract

Amyloid precursor protein (APP) and its family members amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2) are type 1 transmembrane glycoproteins that are highly conserved across species. The transcriptional regulation of APP and APLP2 is similar but not identical, and the cleavage of both proteins is regulated by phosphorylation. APP has been implicated in Alzheimer's disease causation, and in addition to its importance in neurology, APP is deregulated in cancer cells. APLP2 is likewise overexpressed in cancer cells, and APLP2 and APP are linked to increased tumor cell proliferation, migration, and invasion. In this present review, we discuss the unfolding account of these APP family members' roles in cancer progression and metastasis.

Keywords: amyloid precursor protein; amyloid precursor-like protein 2; cancer; growth; migration.

Figure 1. Graphical representations of the domains and sub-domains for APP and APLP2 are shown, along with disulfide bonds and predicted post-translational modifications

A. For APP, the 770 amino acid isoform (UniProt accession number P05067) is displayed. B. For APLP2, the 763 amino acid isoform (UniProt accession number Q06481) is shown. N-glycan prediction was done with the NetNGlyc 1.0 Server (http://www.cbs.dtu.dk/services/NetNGlyc/). O-glycan prediction was performed by NetOGlyc 3.1 Server (http://www.cbs.dtu.dk/services/NetOGlyc/). Phosphorylated residues were predicted with PhosphoSite (http://www.phosphosite.org/homeAction.do). For some isoforms of APLP2, but not of APP, chondroitin sulfate (CS) glycosaminoglycan modification occurs at Serine 614.

Figure 2. Secretase processing of APP and APLP2 generates many fragments

Fragments of APP A. and APLP2 B. generated following cleavage by several secretase enzymes are shown. Amino acids in canonical APP and APLP2 are provided. Double forward slashes are used to denote truncated sequences. The N-terminal ends are indicated with NH₂ and the carboxyl ends are indicated with COOH. A. Beta secretase 1 and 2 (BACE1 and BACE2) can cleave at site β, while the alternate cleavage site for BACE1 is site β’ and the alternative cleavage site for BACE2 is site θ. Two α-secretase cleavage sites have been described, α and α’. Sites γ and ε are cleaved by γ-secretase enzymes. Fragments of APP generated by various cleavage sites are provided with their nomenclature (text inside rectangles) and the residues forming the various fragments (superscript text above rectangles). The C-terminal fragments (CTF) of APP are C99, C89, C83 and C80 and the intracellular domains (ICDs) of APP are C59, C57 and C50. B. The BACE1 (β), ADAM10 (α) and γ-secretase cleavage sites (γ) have been determined for APLP2. APLP2 C-terminal fragments are distinguished by the secretase responsible for their formation. Intracellular domains of APLP2 are denoted as ICDs.

Figure 3. Isoforms of APLP2 arise through alternate splicing

A. Reported isoforms of APLP2 are shown with numbers denoting residues not encoded in smaller isoforms. B. The 18 exons of APLP2 are displayed alongside the residues that they encode. C. Exon junctions in the canonical APLP2 sequence (top row) and known splicing sites (bottom three rows) are depicted. Letters above exons indicate the nucleic acid codes, and residues and their location within the canonical APLP2 isoform are provided.

Figure 4. APP has alternatively spliced isoforms

A. 18 exons encode the canonical 770-amino acid APP uncleaved glycoprotein, with several overlapping residues resulting from ligated mRNA of different exons forming a single codon. B. Diagrams of primary isoforms APP 751, APP 695, and leukocyte (L)-APP 752, with excised residues denoted by black horizontal lines. Excised exons are differentially colored: heparin-binding domain in exon 2 (purple), Kunitz-type protease inhibitor in exon 7 (red), OX-2 antigen sequence in exon 8 (orange), and amyloid beta processing sequence (grey). The deletion of the amyloid beta processing sequence enables the attachment of chondroitin sulfate glycosaminoglycan. C. Alternative splicing events and amino acid substitutions in 8 APP isovariants.

Figure 5. Deregulation of APP and APLP2 causes cancer progression and metastasis, but the roles in cancer of most of the protein interactions involving APP and APLP2 are not well understood

Illustrations of transmembrane APP and APLP2 are displayed with cleavage sites indicated. Proteolytic α-, β-. and γ-secretases cleave at various sites on APP and APLP2, generating protein fragments. Interactions between APP and APLP2 with various interacting partners are mediated by glycosylation and phosphorylation.