Multisite tyrosine phosphorylation of the N‐terminus of Mint1/X11α by Src kinase regulates the trafficking of amyloid precursor protein

Dunning, Christopher J.R.; Black, Hannah L; Andrews, Katie L.; Davenport, Elizabeth C.; Conboy, Michael J.; Chawla, Sangeeta; Dowle, Adam; Ashford, David A.; Thomas, Jerry R.; Evans, Gareth J.

doi:10.1111/jnc.13571

Cited by 27 publications

(23 citation statements)

References 47 publications

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“…Our observations are in agreement with the finding of various mass spectrometric studies, namely, that GULP1 is a phosphoprotein (26)(27)(28). It has been reported that phosphorylation of AIPs alters APP processing, including residues within their PTB domains (14,19,29,30). Five phospho-residues within the GULP1 PTB domain have been reported in several mass spectrometric studies (26)(27)(28).…”

Section: Resultssupporting

confidence: 93%

“…It has been reported that phosphorylation of AIPs alters APP processing, including residues within their PTB domains (14, 19, 29, 30). Five phospho‐residues within the GULP1 PTB domain have been reported in several mass spectrometric studies (26–28).…”

Section: Resultsmentioning

confidence: 99%

“…In vitro kinase assays were performed as previously described (22). GST-GULP1 [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] and GST-GULP1 [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] T35A were expressed in E. coli and purified with glutathione sepharose 4B according to the manufacturer's instructions (GE Healthcare). FLAG-tagged PKCz was isolated by immunoprecipitation using an anti-FLAG antibody (M2) (MilliporeSigma).…”

Section: In Vitro Kinase Assaymentioning

confidence: 99%

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Attenuation of amyloid‐β generation by atypical protein kinase C‐mediated phosphorylation of engulfment adaptor PTB domain containing 1 threonine 35

et al. 2019

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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

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: In Vitro Kinase Assaymentioning

confidence: 99%

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Attenuation of amyloid‐β generation by atypical protein kinase C‐mediated phosphorylation of engulfment adaptor PTB domain containing 1 threonine 35

et al. 2019

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“…This possibility is supported by the fact that mAtg9 can be phosphorylated by Src kinase which facilitates the interaction between Atg9 and AP1/AP2. Because it is known that multiple members of Src kinase family cycle between the plasma membrane, the Golgi complex, and the endosomes [41][42][43], and are involved in the transport of various cargoes between these membrane compartments [44,45]. When it is still unclear why abolishing the Src-dependent phosphorylation that prevents mAtg9 from interacting with AP1 and AP2, can increase mAtg9 on the plasma membrane [31], our data suggest that the phosphorylation contributes to the post-Golgi transport of cathepsin D. The phosphorylation of mAtg9 may occur either on the plasma membrane or on the TGN by activated Src from the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Mammalian Atg9 contributes to the post‐Golgi transport of lysosomal hydrolases by interacting with adaptor protein‐1

et al. 2017

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Accumulating evidence has indicated a role for autophagy-related (Atgs) proteins in cell regulation which is independent of their autophagic activities. As the only known transmembrane protein essential for autophagy, Atg9 cycles between the trans-Golgi network (TGN) and endosomes. Here, we report a function for mammalian Atg9 (mAtg9) in the transport of lysosomal hydrolases which impacts the lysosomal degradation capacity. Depletion of mAtg9 inhibits the degradation of epidermal growth factor receptor and the maturation of cathepsin D and cathepsin L. mAtg9 interacts with adaptor protein-1 (AP1) and the cation-independent mannose-6-phosphate receptor, facilitating AP1 polymerization and the transport of cathepsin D from the TGN. These results suggest that mAtg9 may serve as a coreceptor of lysosomal hydrolases for their TGN export by cycling between the TGN and endosomes.

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“…APP-dependent modulation of synaptic structure and function may occur through alternative splicing of APP or phosphorylation of the APP C-terminus, thereby altering interaction of APP/APLP with their binding proteins (Kyriazis et al, 2008; Tamayev et al, 2009; Dunning et al, 2016). Alternative splicing of APP and its homologs is complex, but detailed investigations in the context of the putative physiological functions of APP are lacking (Pandey et al, 2016).…”

Section: App/aplp Binding Proteins and Synaptic Functionmentioning

confidence: 99%

APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins

Guénette¹,

Strecker

Kins

2017

Front. Mol. Neurosci.

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Understanding the molecular mechanisms underlying amyloid precursor protein family (APP/APP-like proteins, APLP) function in the nervous system can be achieved by studying the APP/APLP interactome. In this review article, we focused on intracellular APP interacting proteins that bind the YENPTY internalization motif located in the last 15 amino acids of the C-terminal region. These proteins, which include X11/Munc-18-interacting proteins (Mints) and FE65/FE65Ls, represent APP cytosolic binding partners exhibiting different neuronal functions. A comparison of FE65 and APP family member mutant mice revealed a shared function for APP/FE65 protein family members in neurogenesis and neuronal positioning. Accumulating evidence also supports a role for membrane-associated APP/APLP proteins in synapse formation and function. Therefore, it is tempting to speculate that APP/APLP C-terminal interacting proteins transmit APP/APLP-dependent signals at the synapse. Herein, we compare our current knowledge of the synaptic phenotypes of APP/APLP mutant mice with those of mice lacking different APP/APLP interaction partners and discuss the possible downstream effects of APP-dependent FE65/FE65L or X11/Mint signaling on synaptic vesicle release, synaptic morphology and function. Given that the role of X11/Mint proteins at the synapse is well-established, we propose a model highlighting the role of FE65 protein family members for transduction of APP/APLP physiological function at the synapse.

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Multisite tyrosine phosphorylation of the N‐terminus of Mint1/X11α by Src kinase regulates the trafficking of amyloid precursor protein

Cited by 27 publications

References 47 publications

Attenuation of amyloid‐β generation by atypical protein kinase C‐mediated phosphorylation of engulfment adaptor PTB domain containing 1 threonine 35

Attenuation of amyloid‐β generation by atypical protein kinase C‐mediated phosphorylation of engulfment adaptor PTB domain containing 1 threonine 35

Mammalian Atg9 contributes to the post‐Golgi transport of lysosomal hydrolases by interacting with adaptor protein‐1

APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins

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