The identification of GSAP as a specific stimulator of APP processing is important in understanding how γ-secretase is regulated and which mechanism enables selection among the various substrates of the γ-secretase activity. Although more than 30 single transmembrane proteins have been reported as γ-secretase substrates, including APP, Notch, and E- and N-cadherins (see Marambaud et al., 2002, and 2003 for cadherins), no consensus sequence is recognized among these substrates. Accordingly, substrate recognition and broad specificity for γ-secretase remain an enigma. It is also noted that the γ-secretase complex detected by glycerol velocity gradient, or blue native-PAGE (Georgakopoulos et al., 1999; Gu et al., 2004; Evin et al., 2005; Kiss et al., 2008), shows an apparent molecular weight larger than 400 kDa, which exceeds the simple sum of the molecular weights of the γ-secretase core components, presenilin (PS)/N- and C-terminal fragments (28 and 18 kDa, respectively), Nicastrin (120 kDa), APH-1 (24 kDa) and PEN-2 (12 kDa). One interesting concept is that adapter proteins act...  Read more

The identification of GSAP as a specific stimulator of APP processing is important in understanding how γ-secretase is regulated and which mechanism enables selection among the various substrates of the γ-secretase activity. Although more than 30 single transmembrane proteins have been reported as γ-secretase substrates, including APP, Notch, and E- and N-cadherins (see Marambaud et al., 2002, and 2003 for cadherins), no consensus sequence is recognized among these substrates. Accordingly, substrate recognition and broad specificity for γ-secretase remain an enigma. It is also noted that the γ-secretase complex detected by glycerol velocity gradient, or blue native-PAGE (Georgakopoulos et al., 1999; Gu et al., 2004; Evin et al., 2005; Kiss et al., 2008), shows an apparent molecular weight larger than 400 kDa, which exceeds the simple sum of the molecular weights of the γ-secretase core components, presenilin (PS)/N- and C-terminal fragments (28 and 18 kDa, respectively), Nicastrin (120 kDa), APH-1 (24 kDa) and PEN-2 (12 kDa). One interesting concept is that adapter proteins act as recruiting factors specific for one, or a subgroup of, substrate(s) and regulate γ-secretase cleavages. We proposed this model in our paper published two years ago (Kouchi et al., 2009).

We have reported p120 catenin, an isoform of δ-catenin, as such a recruiting protein specific for N- and E-cadherins since it has binding affinity to PS1, as well as to these cadherins, and also mediates PS1-dependent cleavage of these substrates (Kouchi et al., 2009; also see Kiss et al., 2008, for investigations on γ-secretase catenin supercomplex). In this model, various recruiting factors could be indispensible for substrate recognition and explain the high-molecular-weight γ-secretase supercomplex(es) with broad substrate specificity.

GSAP reported by He et al. seems to be another example of this kind of protein, but specific for the APP substrate. Interestingly, the interaction between p120 catenin and the cadherins involves the juxtamembrane region of the substrate, i.e., cadherin, just as in the case of GSAP and APP-CTFs. And, just like GSAP, p120 catenin plays the role as a bridge between the γ-secretase and the substrate. We have further identified a p120 binding site in PS1, amino acids 330-360 (Kouchi et al., 2009), although the GSAP binding site has yet to be identified. It is possibly in the PS1 CTF.

Whereas p120 binds to cadherins, but not to APP, expression of p120 catenin not only promoted E-cadherin cleavage but also partially suppressed Aβ and AICD production (Kouchi et al., 2009). We explained this by a possible competition between substrates, i.e., E-cadherin and APP, for limited availability of γ-secretase, but now we can give an alternative interpretation—that p120 catenin and GSAP may competitively bind to the cytoplasmic loop region of PS1CTF. Since cadherins and p120 are implicated in dendritic spine formation and synaptic transmission, it seems to be a crucial issue whether GSAP affects cadherin/p120-catenin/PS interaction in order to validate GSAP as an attractive target for treatment of AD.

References:
Evin G, Canterford LD, Hoke DE, Sharples RA, Culvenor JG, Masters CL. Transition-state analogue gamma-secretase inhibitors stabilize a 900 kDa presenilin/nicastrin complex. Biochemistry. 2005 Mar 22;44(11):4332-41. Abstract

Georgakopoulos A, Marambaud P, Efthimiopoulos S, Shioi J, Cui W, Li HC, Schütte M, Gordon R, Holstein GR, Martinelli G, Mehta P, Friedrich VL Jr, Robakis NK. Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Mol Cell. 1999 Dec;4(6):893-902. Abstract

Gu Y, Sanjo N, Chen F, Hasegawa H, Petit A, Ruan X, Li W, Shier C, Kawarai T, Schmitt-Ulms G, Westaway D, St George-Hyslop P, Fraser PE. The presenilin proteins are components of multiple membrane-bound complexes that have different biological activities. J Biol Chem. 2004 Jul 23;279(30):31329-36. Abstract

Kiss A, Troyanovsky RB, Troyanovsky SM. p120-catenin is a key component of the cadherin-gamma-secretase supercomplex. Mol Biol Cell. 2008 Oct;19(10):4042-50. Abstract

Kouchi Z, Barthet G, Serban G, Georgakopoulos A, Shioi J, Robakis NK. p120 catenin recruits cadherins to gamma-secretase and inhibits production of Abeta peptide. J Biol Chem. 2009 Jan 23;284(4):1954-61. Abstract

Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell. 2003 Sep 5;114(5):635-45. Abstract

Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, Wisniewski T, Robakis NK. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 2002 Apr 15;21(8):1948-56. Abstract

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