Amyloid‐β (Aβ) is derived from the proteolytic processing of amyloid precursor protein (APP), and the deposition of extracellular Aβ to form amyloid plaques is a pathologic hallmark of Alzheimer's disease (AD). Although reducing Aβ generation and accumulation has been proposed as a means of treating the disease, adverse side effects and unsatisfactory efficacy have been reported in several clinical trials that sought to lower Aβ levels. Engulfment adaptor phosphotyrosine‐binding (PTB) domain containing 1 (GULP1) is a molecular adaptor that has been shown to interact with APP to alter Aβ production. Therefore, the modulation of the GULP1‐APP interaction may be an alternative approach to reducing Aβ. However, the mechanisms that regulate GULP1‐APP binding remain elusive. As GULP1 is a phosphoprotein, and because phosphorylation is a common mechanism that regulates protein interaction, we anticipated that GULP1 phosphorylation would influence GULP1‐APP interaction and thereby Aβ production. We show here that the phosphorylation of GULP1 threonine 35 (T35) reduces GULP1‐APP interaction and suppresses the stimulatory effect of GULP1 on APP processing. The residue is phosphorylated by an isoform of atypical PKC (PKCζ). Overexpression of PKCζ reduces both GULP1‐APP interaction and GULP1‐mediated Aβ generation. Moreover, the activation of PKCζ via insulin suppresses APP processing. In contrast, GULP1‐mediated APP processing is enhanced in PKCζ knockout cells. Similarly, PKC ɩ,*** another member of atypical PKC, also decreases GULP1‐mediated APP processing. Intriguingly, our X‐ray crystal structure of GULP1 PTB‐APP intracellular domain (AICD) peptide reveals that GULP1T35 is not located at the GULP1‐AICD binding interface; rather, it immediately precedes the β1‐α2loop that forms a portion of the binding groove for the APP helix αC. Phosphorylating the residue may induce an allosteric effect on the conformation of the binding groove. Our results indicate that GULP1 T35 phosphorylation is a mechanism for the regulation of GULP1‐APP interaction and thereby APP processing. Moreover, the activation of atypical PKC, such as by insulin, may confer a beneficial effect on AD by lowering GULP1‐mediated Ap production.—Chau, D. D.‐L., Yung K. W.‐Y., Chan, W. W.‐L., An, Y., Hao, Y., Chan, H.‐Y. E., Ngo, J. C.‐K., Lau, K.‐F. Attenuation of amyloid‐β generation by atypical protein kinase C‐mediated phosphorylation of engulfment adaptor PTB domain containing 1 threonine 35. FASEB J. 33, 12019‐12035 (2019). http://www.fasebj.org

Amyloid precursor protein (APP) is a key molecule in the pathogenesis of Alzheimer's disease (AD) as the pathogenic amyloid-β peptide is derived from it. Two closely related APP family proteins (APPs) have also been identified in mammals. Current knowledge, including genetic analyses of gain- and loss-of-function mutants, highlights the importance of APPs in various physiological functions. Notably, APPs consist of multiple extracellular and intracellular protein-binding regions/domains. Protein–protein interactions are crucial for many cellular processes. In past decades, many APPs interactors have been identified which assist the revelation of the putative roles of APPs. Importantly, some of these interactors have been shown to influence several APPs-mediated neuronal processes which are found defective in AD and other neurodegenerative disorders. Studying APPs–interactor complexes would not only advance our understanding of the physiological roles of APPs but also provide further insights into the association of these processes to neurodegeneration, which may lead to the development of novel therapies. In this mini-review, we summarize the roles of APPs–interactor complexes in neurodevelopmental processes including neurogenesis, neurite outgrowth, axonal guidance and synaptogenesis.

Neurite outgrowth is a fundamental process in neurons that produces extensions and, consequently, neural connectivity. Neurite damage and atrophy are observed in various brain injuries and disorders. Understanding the intrinsic pathways of neurite outgrowth is essential for developing strategies to stimulate neurite regeneration.Insulin is a pivotal hormone in the regulation of glucose homeostasis. There is increasing evidence for the neurotrophic functions of insulin, including the induction of neurite outgrowth. However, the associated mechanism remains elusive. Here, we demonstrate that insulin potentiates neurite outgrowth mediated by the small GTPases ADP-ribosylation factor 6 (ARF6) and Ras-related C3 botulinum toxin substrate 1 (Rac1) through the neuronal adaptor FE65. Moreover, insulin enhances atypical protein kinase Cι/λ (PKCι/λ) activation and FE65 phosphorylation at serine 459 (S459) in neurons and mouse brains. In vitro and cellular assays show that PKCι/λ phosphorylated FE65 at S459. Consistently, insulin potentiates FE65 S459 phosphorylation only in the presence of PKCι/λ. Phosphomimetic studies show that an FE65 S459E mutant potently activates ARF6, Rac1, and neurite outgrowth. Notably, this phosphomimetic mutation enhances the FE65-ARF6 interaction, a process that promotes ARF6-Rac1-mediated neurite outgrowth. Likewise, insulin treatment and PKCι/λ overexpression potentiate the FE65-ARF6 interaction. Conversely, PKCι/λ

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