Regulatory Network in Protein Phosphorylation
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Substrate: APP

Description: Amyloid beta A4 protein precursor (APP) (ABPP) (Alzheimer diseaseamyloid protein) (Cerebral vascular amyloid peptide) (CVAP) (Proteasenexin-II) (PN-II) (APPI) (PreA4) [Contains: Soluble APP-alpha (S-APP-alpha); Soluble APP-beta (S-APP-beta); C99; Beta-amyloid protein 42(Beta-APP42); Beta-amyloid protein 40 (Beta-APP40); C83; P3(42);P3(40); Gamma-CTF(59) (Gamma-secretase C-terminal fragment 59)(Amyloid intracellular domain 59) (AID(59)) (AICD-59); Gamma-CTF(57)(Gamma-secretase C-terminal fragment 57) (Amyloid intracellular domain57) (AID(57)) (AICD-57); Gamma-CTF(50) (Gamma-secretase C-terminalfragment 50) (Amyloid intracellular domain 50) (AID(50)) (AICD-50);C31].

Synonyms: A4, AD1

Ensembl ID: ENSG00000142192

UniprotKB/SwissProt: A4_HUMAN (P05067)

Function: Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1/Tip60 and inhibit Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity). The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.

Other Modifications: View all modification sites in dbPTM

Protein Subcellular Localization: Membrane; Single-pass type I membrane protein. Note=Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where comple
PDB:1AAP
Protein Domain and Phosphorylation Sites:

The phosphorylated sites of APP

No.SubstrateUniProtKB IDPositionPhosphoPeptideSolvent AccessibilityCatalytic kinaseSourceComputational Annotation of Catalytic KinaseInteracting PartnersExpression Analysis
1APPA4_HUMANS198SDNVD S ADAEE 24.62%CK2_group Swiss-Prot 55.0  ViewAnalyzing
2APPA4_HUMANS206AEEDD S DVWWG 46.51%CK1_group Swiss-Prot 55.0  ViewAnalyzing
3APPA4_HUMANT729KKKQY T SIHHG 20.79% Swiss-Prot 55.0 (Similarity)View   
4APPA4_HUMANS730KKQYT S IHHGV 18.26%APP-kinase I  Swiss-Prot 55.0 (Similarity) ViewAnalyzing
5APPA4_HUMANT743VDAAV T PEERH 21.91%Q9Y5Z0(Beta site APP cleaving enzyme 2) HPRD:00100(in vitro;in vivo) ViewAnalyzing
6APPA4_HUMANT743VDAAV T PEERH 21.91%GSK3B(GSK3 beta) Phospho.ELM 7.0 ViewAnalyzing
7APPA4_HUMANT743VDAAV T PEERH 21.91%CDK5 HPRD:00100(in vitro;in vivo)  ViewAnalyzing
8APPA4_HUMANT743VDAAV T PEERH 21.91%JNK3(MAPK10) Swiss-Prot 55.0  ViewAnalyzing
9APPA4_HUMANT743VDAAV T PEERH 21.91%CDK5 Swiss-Prot 55.0   ViewAnalyzing
10APPA4_HUMANT743VDAAV T PEERH 21.91%GSK3B HPRD:00100(in vitro;in vivo)  ViewAnalyzing
11APPA4_HUMANY757MQQNG Y ENPTY 21.78% Phospho.ELM 7.0View   
12APPA4_HUMANY757MQQNG Y ENPTY 21.78% Swiss-Prot 55.0 (Similarity)View   
13APPA4_HUMANY757MQQNG Y ENPTY 21.78% HPRD:00100(in vitro;in vivo)View