Table 1.

Reported phosphorylation sites of APP695 and its effects.

Phosphorylation Site	Kinases/Signaling Pathways	Reported Effects	References
Threonine 654	CaMKII	N.D. 1	[55]
	ROCK2	Blocking T654 phosphorylation; promoting BACE1 relocation from endosomes to lysosomes and APP trafficking to lysosomes; reducing Aβ generation when inhibited	[56]
Serine 655	PKC, CaMKII	Increasing the secretion of APP into cerebrospinal fluid and decreasing the cleavage of mature APP; enhancing APP secretory traffic when activated	[55,57,58,59]
	ROCK1	Enhancing the interaction between BACE1 and APP and promoting Aβ generation when activated	[60]
	APP kinase I	Putatively modulating the internalization of APP when activated	[61]
Threonine 668	CDC2 kinase	Increasing the content of immature APP and C-terminal fragments while reducing the level of secreted APP products when activated	[40]
	CDK5	Enhancing the secretion of Aβ, sAPPβ, and sAPPα; enriching APP in endosomes when activated	[43,44,49]
	GSK-3β	Affecting copper-induced APP trafficking to axons	[41,42]
	JNK	Inducing APP degradation, lowering sAPPβ and Aβ generation, and promoting non-amyloidogenic processing when inhibited	[46,51,52]
	JIP-3-JNK	Phosphorylating APP and transporting pAPP to neuritis when activated	[50]
	DAPK1	Shifting APP toward non-amyloidogenic pathway and decreasing Aβ generation when inhibited	[54,62]
	LRRK2	Elevating the nuclear translocation of AICD and its transcriptional activity and exacerbating dopaminergic neurons when activated	[63]
	Plk2	Accelerating APP amyloidogenic cleavage by β-secretase at synapses when activated	[64]
Serine 675	Plk2	Stimulating the endocytosis of APP and driving the BACE1 cleavage; promoting meprin β mediated APP processing when activated	[64]
Tyrosine 682	Abl	Phosphorylating APP and forming stable complexes with pAPP; affecting APP binding to FE65 and X11 when activated	[65]
	Src	Increasing the formation of pAPP-Grb2 complexes when activated	[66]
	NGF-TrkA	Reducing the generation of the AICD; regulating the subcellular distribution and activation of TrkA when activated	[67,68]
	Fyn	Affecting the correct APP trafficking and sorting in neurons and the binding with clathrin and AP2 when activated	[69]
Tyrosine 687	Tyrosine kinase	Retaining APP in ER and TGN and decreasing its turnover rate; reducing Aβ formation when activated	[70,71]
Tyrosine 653	N.D.	N.D.	[38]
Threonine 686	N.D.	N.D.	[38]
Serine 198 and serine 206	CK-1 and CK-2-like ectoprotein kinases	Essential for the correct location of APP on the cell surface	[72,73]

Abbreviations: ¹ N.D: not defined in the literature; CaMKII: Ca²⁺/calmodulin-dependent protein kinase II; ROCK2: Rho-associated coiled-coil kinase 2; BACE1: β-site APP-cleaving enzyme 1; APP: amyloid precursor protein; Aβ: amyloid-β; PKC: protein kinase C; ROCK1: Rho-associated coiled-coil kinase 1; CDC2: p34cdc2 protein kinase; CDK5: cyclin-dependent kinase 5; sAPPβ; soluble APPβ; sAPPα: soluble APPα; GSK-3β: glycogen synthesis kinase-3β; JNK: c-Jun N-terminal kinase; JIP-3: JNK-interacting protein 3; DAPK1: death-associated protein kinase 1; LRRK2: leucine-rich repeat kinase 2; AICD: APP intracellular domain; NGF: nerve growth factor; ER: endoplasmic reticulum; TGN: trans-Golgi network; CK: casein kinase.