Engulfment adapter PTB domain containing 1 interacts with and affects processing of the amyloid-β precursor protein

The apoptotic engulfment protein Ced-6 participates in clathrin-mediated yolk uptake inDrosophilaegg chambers

“…In fact, mammalian GULP binds to clathrin (Martins-Silva et al , 2006; Figure 3B), and, similar to Ced-6-GFP, ectopic GULP-GFP (Kiss et al , 2006) localizes to AP-2–positive structures in HeLa cells (Figure 9A). Given published evidence (Kiss et al , 2006; Martins-Silva et al , 2006; Beyer et al , 2012), it was unexpected that transiently transfected GULP similarly clusters at AP-2–positive surface patches in addition to a diffuse cytosolic pool. Yet the punctate distribution resembles the “granular” staining of endogenous GULP in U-2 OS and U-215 MG cells in the Human Protein Atlas (Uhlen et al , 2010).…”

“…Similar results are obtained with GULP-GFP and tdRFP-GULP coexpression (Supplemental Figure S7); the general deposition of GULP at clathrin-coated structures is therefore not affected by the positioning of the fused fluorescent reporter. Although GULP has been localized to intracellular vesicular elements (Kiss et al , 2006; Martins-Silva et al , 2006; Beyer et al , 2012), extensive colocalization with AP-2 and clathrin at the plasma membrane is entirely consistent with the coat protein–binding features seen in biochemical assays (Figure 3B); even presuming that the GULP PTB domain similarly engages PtdIns(4,5)P 2 and is known to bind to FXNPXY signals (Su et al , 2002; Park et al , 2008, 2010), these interactions alone will not place GULP physically in clathrin-coated structures at steady state (Mishra et al , 2002a; Chetrit et al , 2008). …”

“…Gulp (and Ced-6) has a wide expression pattern (Liu and Hengartner, 1999; Smits et al , 1999; Hao et al , 2011; Beyer et al , 2012), but endogenous GULP is difficult to detect in HeLa cells (Hao et al , 2011). Placenta is a source of many GULP ESTs and at least five cDNAs; a ∼35-kDa protein, commonly detected by four independent anti-GULP antibodies, is present in placenta cytosol (Figure 9D).…”

“…Coincidentally, the placental trophoblast plays a vital role in embryonic nutrient supply from the maternal circulation. Furthermore, the mammalian Gulp PTB domain binds physically to LRP1 (Kiss et al , 2006), stabilin-2 (Park et al , 2008), and amyloid precursor protein (Hao et al , 2011; Beyer et al , 2012)—all transmembrane proteins well established to undergo clathrin-dependent endocytosis (Li et al , 2001; Thinakaran and Koo, 2008; Figure 10). However, in brain—also a source of Gulp transcripts (Liu and Hengartner, 1999; Martins-Silva et al , 2006)—the protein is undetectable in either cytosol or coated vesicles.…”

Engulfment adaptor phosphotyrosine-binding-domain-containing 1 (GULP1) is a nucleocytoplasmic shuttling protein and is transactivationally active together with low-density lipoprotein receptor-related protein 1 (LRP1)

“…The proximal PTB domain binds to APP’s NPxY-motif [14], while the distal PTB domain of Fe65 can interact with one or both LRP1 NPxY-motifs [4, 15]. We and others have recently identified a novel intracellular APP adaptor protein, engulfment adapter phosphotyrosine binding domain containing 1 (GULP1) [16-17], the human homologue of C. elegans death (CED)-6, whose function in engulfment is highly conserved among species. GULP1 acts as a promoter of phagocytosis in human macrophages and might function as a signaling adaptor downstream of CED-1.…”