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Entry version 281 (10 Apr 2019)
Sequence version 3 (01 Nov 1991)
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Protein

Amyloid-beta precursor protein

Gene

APP

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score:

Annotation score:5 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>
-Experimental evidence at protein leveli <p>This indicates the type of evidence that supports the existence of the protein. Note that the ‘protein existence’ evidence does not give information on the accuracy or correctness of the sequence(s) displayed.<p><a href='/help/protein_existence' target='_top'>More...</a></p>

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis (PubMed:25122912). Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits 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 Cu2+-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. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu2+ ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.By similarity1 Publication
Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu2+ and Fe3+ to Cu+ and Fe2+, respectively. Amyloid-beta protein 42 is a more effective reductant than amyloid-beta protein 40. Amyloid-beta peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. APP42-beta 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. Also binds GPC1 in lipid rafts.
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.
N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).

Miscellaneous

Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. The affinity for copper is much higher than for other transient metals and is increased under acidic conditions. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Function’ section indicates at which position the protein binds a given metal ion. The nature of the metal is indicated in the ‘Description’ field.<p><a href='/help/metal' target='_top'>More...</a></p>Metal bindingi147Copper 1PROSITE-ProRule annotationCombined sources2 Publications1
Metal bindingi151Copper 1PROSITE-ProRule annotationCombined sources2 Publications1
Metal bindingi168Copper 1PROSITE-ProRule annotationCombined sources1 Publication1
<p>This subsection describes interesting single amino acid sites on the sequence that are not defined in any other subsection. This subsection can be displayed in different sections (‘Function’, ‘PTM / Processing’, ‘Pathology and Biotech’) according to its content.<p><a href='/help/site' target='_top'>More...</a></p>Sitei170Required for Cu(2+) reductionPROSITE-ProRule annotation1
Sitei301 – 302Reactive bond2
Metal bindingi677Copper or zinc 22 Publications1
Metal bindingi681Copper or zinc 22 Publications1
Metal bindingi684Copper or zinc 23 Publications1
Metal bindingi685Copper or zinc 22 Publications1
Sitei704Implicated in free radical propagationBy similarity1
Sitei706Susceptible to oxidation1 Publication1

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

GO - Biological processi

<p>UniProtKB Keywords constitute a <a href="http://www.uniprot.org/keywords">controlled vocabulary</a> with a hierarchical structure. Keywords summarise the content of a UniProtKB entry and facilitate the search for proteins of interest.<p><a href='/help/keywords' target='_top'>More...</a></p>Keywordsi

Molecular functionHeparin-binding, Protease inhibitor, Serine protease inhibitor
Biological processApoptosis, Cell adhesion, Endocytosis, Notch signaling pathway
LigandCopper, Iron, Metal-binding, Zinc

Enzyme and pathway databases

BioCyc Collection of Pathway/Genome Databases

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BioCyci
MetaCyc:ENSG00000142192-MONOMER

Reactome - a knowledgebase of biological pathways and processes

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Reactomei
R-HSA-114608 Platelet degranulation
R-HSA-3000178 ECM proteoglycans
R-HSA-381426 Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-416476 G alpha (q) signalling events
R-HSA-418594 G alpha (i) signalling events
R-HSA-432720 Lysosome Vesicle Biogenesis
R-HSA-444473 Formyl peptide receptors bind formyl peptides and many other ligands
R-HSA-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
R-HSA-844456 The NLRP3 inflammasome
R-HSA-879415 Advanced glycosylation endproduct receptor signaling
R-HSA-8862803 Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models
R-HSA-8957275 Post-translational protein phosphorylation
R-HSA-933542 TRAF6 mediated NF-kB activation
R-HSA-977225 Amyloid fiber formation

SABIO-RK: Biochemical Reaction Kinetics Database

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SABIO-RKi
P05067

SIGNOR Signaling Network Open Resource

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SIGNORi
P05067

Protein family/group databases

MEROPS protease database

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MEROPSi
I02.015

Transport Classification Database

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TCDBi
1.C.50.1.2 the amyloid Beta-protein peptide (aBetapp) family

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides an exhaustive list of all names of the protein, from commonly used to obsolete, to allow unambiguous identification of a protein.<p><a href='/help/protein_names' target='_top'>More...</a></p>Protein namesi
Recommended name:
Amyloid-beta precursor proteinCurated
Short name:
APPCurated
Alternative name(s):
ABPP
APPI
Alzheimer disease amyloid protein
Amyloid precursor proteinCurated
Amyloid-beta A4 protein
Cerebral vascular amyloid peptide
Short name:
CVAP
PreA4
Protease nexin-II
Short name:
PN-II
Cleaved into the following 14 chains:
Soluble APP-alpha1 Publication
Short name:
S-APP-alpha1 Publication
Soluble APP-beta1 Publication
Short name:
S-APP-beta1 Publication
Alternative name(s):
Beta-secretase C-terminal fragment1 Publication
Short name:
Beta-CTF1 Publication
Amyloid-beta protein 421 Publication
Short name:
Abeta42
Alternative name(s):
Beta-APP42
Amyloid-beta protein 401 Publication
Short name:
Abeta40
Alternative name(s):
Beta-APP40
Alternative name(s):
Alpha-secretase C-terminal fragment1 Publication
Short name:
Alpha-CTF1 Publication
Alternative name(s):
Amyloid intracellular domain 59
Short name:
AICD-59
Short name:
AID(59)
Gamma-CTF(59)
Alternative name(s):
Amyloid intracellular domain 57
Short name:
AICD-57
Short name:
AID(57)
Gamma-CTF(57)
Alternative name(s):
Amyloid intracellular domain 50
Short name:
AICD-50
Short name:
AID(50)
Gamma-CTF(50)
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section indicates the name(s) of the gene(s) that code for the protein sequence(s) described in the entry. Four distinct tokens exist: ‘Name’, ‘Synonyms’, ‘Ordered locus names’ and ‘ORF names’.<p><a href='/help/gene_name' target='_top'>More...</a></p>Gene namesi
Name:APPImported
Synonyms:A4, AD1
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides information on the name(s) of the organism that is the source of the protein sequence.<p><a href='/help/organism-name' target='_top'>More...</a></p>OrganismiHomo sapiens (Human)
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section shows the unique identifier assigned by the NCBI to the source organism of the protein. This is known as the ‘taxonomic identifier’ or ‘taxid’.<p><a href='/help/taxonomic_identifier' target='_top'>More...</a></p>Taxonomic identifieri9606 [NCBI]
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section contains the taxonomic hierarchical classification lineage of the source organism. It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first.<p><a href='/help/taxonomic_lineage' target='_top'>More...</a></p>Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section is present for entries that are part of a <a href="http://www.uniprot.org/proteomes">proteome</a>, i.e. of a set of proteins thought to be expressed by organisms whose genomes have been completely sequenced.<p><a href='/help/proteomes_manual' target='_top'>More...</a></p>Proteomesi
  • UP000005640 <p>A UniProt <a href="http://www.uniprot.org/manual/proteomes_manual">proteome</a> can consist of several components. <br></br>The component name refers to the genomic component encoding a set of proteins.<p><a href='/help/proteome_component' target='_top'>More...</a></p> Componenti: Chromosome 21

Organism-specific databases

Eukaryotic Pathogen Database Resources

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EuPathDBi
HostDB:ENSG00000142192.20

Human Gene Nomenclature Database

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HGNCi
HGNC:620 APP

Online Mendelian Inheritance in Man (OMIM)

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MIMi
104760 gene

neXtProt; the human protein knowledge platform

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neXtProti
NX_P05067

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte & Seán O’Donoghue; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular_location_section">'Subcellular location'</a> section describes the subcellular compartment where each non-membrane region of a membrane-spanning protein is found.<p><a href='/help/topo_dom' target='_top'>More...</a></p>Topological domaini18 – 701ExtracellularCuratedAdd BLAST684
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular_location_section">'Subcellular location'</a> section describes the extent of a membrane-spanning region of the protein. It denotes the presence of both alpha-helical transmembrane regions and the membrane spanning regions of beta-barrel transmembrane proteins.<p><a href='/help/transmem' target='_top'>More...</a></p>Transmembranei702 – 722Helical3 PublicationsAdd BLAST21
Topological domaini723 – 770CytoplasmicCuratedAdd BLAST48

Keywords - Cellular componenti

Amyloid, Cell membrane, Cell projection, Coated pit, Cytoplasm, Cytoplasmic vesicle, Endosome, Membrane, Nucleus, Secreted

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

<p>This subsection of the ‘Pathology and Biotech’ section provides information on the disease(s) associated with genetic variations in a given protein. The information is extracted from the scientific literature and diseases that are also described in the <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim">OMIM</a> database are represented with a <a href="http://www.uniprot.org/diseases">controlled vocabulary</a> in the following way:<p><a href='/help/involvement_in_disease' target='_top'>More...</a></p>Involvement in diseasei

Alzheimer disease 1 (AD1)30 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.
See also OMIM:104300
Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Sequence’ section describes natural variant(s) of the protein sequence.<p><a href='/help/variant' target='_top'>More...</a></p>Natural variantiVAR_000015670 – 671KM → NL in AD1; Swedish mutation; highly increases hydrolysis by BACE1 and amyloid-beta proteins production. 4 PublicationsCorresponds to variant dbSNP:rs281865161Ensembl.2
Natural variantiVAR_044424678D → N in AD1. 1 PublicationCorresponds to variant dbSNP:rs63750064EnsemblClinVar.1
Natural variantiVAR_000016692A → G in AD1; Flemish mutation; increases the solubility of processed amyloid-beta peptides and increases the stability of peptide oligomers. 3 PublicationsCorresponds to variant dbSNP:rs63750671EnsemblClinVar.1
Natural variantiVAR_014215693E → G in AD1. 2 PublicationsCorresponds to variant dbSNP:rs63751039EnsemblClinVar.1
Natural variantiVAR_000019713A → T in AD1. 2 PublicationsCorresponds to variant dbSNP:rs63750066EnsemblClinVar.1
Natural variantiVAR_032277714T → A in AD1. 1 PublicationCorresponds to variant dbSNP:rs63750643EnsemblClinVar.1
Natural variantiVAR_014218714T → I in AD1; increased amyloid-beta protein 42/40 ratio. 2 PublicationsCorresponds to variant dbSNP:rs63750973EnsemblClinVar.1
Natural variantiVAR_010108715V → M in AD1; decreased amyloid-beta protein 40/total amyloid-beta. 1 PublicationCorresponds to variant dbSNP:rs63750734EnsemblClinVar.1
Natural variantiVAR_000020716I → V in AD1. 1 PublicationCorresponds to variant dbSNP:rs63750399EnsemblClinVar.1
Natural variantiVAR_000023717V → F in AD1; increased amyloid-beta protein 42/40 ratio. 5 PublicationsCorresponds to variant dbSNP:rs63750264EnsemblClinVar.1
Natural variantiVAR_000022717V → G in AD1; increased amyloid-beta protein 42/40 ratio. 3 PublicationsCorresponds to variant dbSNP:rs63749964EnsemblClinVar.1
Natural variantiVAR_000021717V → I in AD1; increased amyloid-beta protein 42/40 ratio. 9 PublicationsCorresponds to variant dbSNP:rs63750264EnsemblClinVar.1
Natural variantiVAR_014219717V → L in AD1. 1 PublicationCorresponds to variant dbSNP:rs63750264EnsemblClinVar.1
Natural variantiVAR_010109723L → P in AD1. 1 PublicationCorresponds to variant dbSNP:rs63751122EnsemblClinVar.1
Cerebral amyloid angiopathy, APP-related (CAA-APP)5 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.
See also OMIM:605714
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_014216693E → K in CAA-APP; Italian type. 1 PublicationCorresponds to variant dbSNP:rs63750579EnsemblClinVar.1
Natural variantiVAR_000017693E → Q in CAA-APP; Dutch type. 1 PublicationCorresponds to variant dbSNP:rs63750579EnsemblClinVar.1
Natural variantiVAR_014217694D → N in CAA-APP; Iowa type. 2 PublicationsCorresponds to variant dbSNP:rs63749810EnsemblClinVar.1
Natural variantiVAR_032276705L → V in CAA-APP; Italian type. 1 PublicationCorresponds to variant dbSNP:rs63750921EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/manual/pathology_and_biotech_section">'Pathology and Biotech'</a> section describes the effect of the experimental mutation of one or more amino acid(s) on the biological properties of the protein.<p><a href='/help/mutagen' target='_top'>More...</a></p>Mutagenesisi99 – 102KRGR → NQGG: Reduced heparin-binding. 1 Publication4
Mutagenesisi108H → A: Loss of the copper binding site in the GFLD subdomain; when associated with A-110. 1 Publication1
Mutagenesisi110H → A: Loss of the copper binding site in the GFLD subdomain; when associated with A-108. 1 Publication1
Mutagenesisi137H → N: Binds copper. Forms dimer. 1 Publication1
Mutagenesisi141M → T: Binds copper. Forms dimer. 1 Publication1
Mutagenesisi144C → S: Binds copper. No dimer formation. No copper reducing activity. 2 Publications1
Mutagenesisi147 – 149HLH → ALA: 50% decrease in copper reducing activity. 1 Publication3
Mutagenesisi147H → A: Loss of a copper binding site; when associated with A-151. 1 Publication1
Mutagenesisi147H → A: Some decrease in copper reducing activity. 2 Publications1
Mutagenesisi147H → N: Binds copper. Forms dimer. 2 Publications1
Mutagenesisi147H → Y: Greatly reduced copper-mediated low-density lipoprotein oxidation. 2 Publications1
Mutagenesisi151H → A: Loss of a copper binding site; when associated with A-147. 1 Publication1
Mutagenesisi151H → K: Greatly reduced copper-mediated low-density lipoprotein oxidation. 2 Publications1
Mutagenesisi151H → N: Binds copper. Forms dimer. 2 Publications1
Mutagenesisi198S → A: Greatly reduced casein kinase phosphorylation. 2 Publications1
Mutagenesisi206S → A: Reduced casein kinase phosphorylation. 2 Publications1
Mutagenesisi499R → A: Reduced affinity for heparin; when associated with A-503. 1 Publication1
Mutagenesisi503K → A: Reduced affinity for heparin; when associated with A-499. 1 Publication1
Mutagenesisi656S → A: Abolishes chondroitin sulfate binding in L-APP733 isoform. 1 Publication1
Mutagenesisi676R → G: 60-70% zinc-induced amyloid-beta protein 28 aggregation. 1 Publication1
Mutagenesisi681Y → F: 60-70% zinc-induced amyloid-beta protein 28 aggregation. 1 Publication1
Mutagenesisi684H → R: Only 23% zinc-induced amyloid-beta protein 28 aggregation. 1 Publication1
Mutagenesisi695V → C: Causes formation of an artifactual disulfide bond with PSEN1. 1 Publication1
Mutagenesisi704G → V: Reduced protein oxidation. No hippocampal neuron toxicity. 1
Mutagenesisi706M → L: Reduced lipid peroxidation inhibition. 2 Publications1
Mutagenesisi706M → V: No free radical production. No hippocampal neuron toxicity. 2 Publications1
Mutagenesisi717V → C or S: Unchanged amyloid-beta protein 42/total amyloid-beta ratio. 2 Publications1
Mutagenesisi717V → K: Decreased amyloid-beta protein 42/total amyloid-beta ratio. 2 Publications1
Mutagenesisi717V → M: Increased amyloid-beta protein 42/40 ratio. No change in apoptosis after caspase cleavage. 2 Publications1
Mutagenesisi728Y → A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in amyloid-beta protein 42 secretion. 3 Publications1
Mutagenesisi739D → A: No cleavage by caspases during apoptosis. 3 Publications1
Mutagenesisi739D → N: No effect on FADD-induced apoptosis. 3 Publications1
Mutagenesisi743T → A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension. 4 Publications1
Mutagenesisi743T → E: Reduced NGF-stimulated neurite extension. No effect on APP maturation. 4 Publications1
Mutagenesisi756G → A: APP internalization unchanged. No change in amyloid-beta protein 42 secretion. 1 Publication1
Mutagenesisi757Y → A: Little APP internalization. Reduced amyloid-beta protein 42 secretion. 4 Publications1
Mutagenesisi757Y → G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1. 4 Publications