PNCK

gene
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Also known as MGC45419CaMK1b

Summary

PNCK (pregnancy up-regulated nonubiquitous CaM kinase, HGNC:13415) is a protein-coding gene on chromosome Xq28, encoding Calcium/calmodulin-dependent protein kinase type 1B (Q6P2M8). Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade.

PNCK is a member of the calcium/calmodulin-dependent protein kinase family of protein serine/threonine kinases (see CAMK1; MIM 604998) (Gardner et al., 2000 [PubMed 10673339]).

Source: NCBI Gene 139728 — RefSeq curated summary.

At a glance

  • Clinical variants (ClinVar): 63 total
  • Druggable target: yes
  • MANE Select transcript: NM_001366977

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:13415
Approved symbolPNCK
Namepregnancy up-regulated nonubiquitous CaM kinase
LocationXq28
Locus typegene with protein product
StatusApproved
AliasesMGC45419, CaMK1b
Ensembl geneENSG00000130822
Ensembl biotypeprotein_coding
OMIM300680
Entrez139728

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 33 protein_coding, 10 retained_intron, 6 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000340888, ENST00000370142, ENST00000370145, ENST00000370150, ENST00000411968, ENST00000418241, ENST00000419804, ENST00000422811, ENST00000423545, ENST00000425526, ENST00000433470, ENST00000434652, ENST00000438984, ENST00000439087, ENST00000447676, ENST00000458354, ENST00000460106, ENST00000462280, ENST00000463548, ENST00000465303, ENST00000466074, ENST00000466638, ENST00000466662, ENST00000472324, ENST00000473680, ENST00000473831, ENST00000475172, ENST00000480693, ENST00000484705, ENST00000488168, ENST00000488994, ENST00000489536, ENST00000870375, ENST00000870376, ENST00000870377, ENST00000870378, ENST00000870379, ENST00000870380, ENST00000922477, ENST00000922478, ENST00000922479, ENST00000922480, ENST00000955616, ENST00000955617, ENST00000955618, ENST00000955619, ENST00000955620, ENST00000955621, ENST00000955622, ENST00000955623, ENST00000955624

RefSeq mRNA: 8 — MANE Select: NM_001366977 NM_001039582, NM_001135740, NM_001366975, NM_001366976, NM_001366977, NM_001366978, NM_001366979, NM_001366980

CCDS: CCDS35503, CCDS48189, CCDS94698

Canonical transcript exons

ENST00000340888 — 12 exons

ExonStartEnd
ENSE00001451966153673780153673813
ENSE00003462640153671078153671190
ENSE00003477012153670918153670996
ENSE00003505261153673009153673078
ENSE00003563141153671880153672018
ENSE00003571548153670450153670594
ENSE00003612816153671549153671672
ENSE00003620909153671285153671360
ENSE00003653614153670744153670831
ENSE00003660164153672126153672200
ENSE00003692536153672566153672697
ENSE00003900260153669733153670130

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 96.24.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9891 / max 97.3695, expressed in 273 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter IDTPM avgSamples expressed
2008941.1009229
2008910.257577
2008950.166474
2008970.152049
2008960.142471
2008930.106669
2008920.063442

Top tissues by expression

245 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
right frontal lobeUBERON:000281096.24gold quality
Brodmann (1909) area 9UBERON:001354096.20gold quality
nucleus accumbensUBERON:000188296.16gold quality
anterior cingulate cortexUBERON:000983595.84gold quality
muscle layer of sigmoid colonUBERON:003580595.68gold quality
amygdalaUBERON:000187694.36gold quality
caudate nucleusUBERON:000187393.85gold quality
putamenUBERON:000187493.74gold quality
prefrontal cortexUBERON:000045193.67gold quality
hypothalamusUBERON:000189892.94gold quality
dorsolateral prefrontal cortexUBERON:000983492.72gold quality
esophagogastric junction muscularis propriaUBERON:003584192.64gold quality
frontal cortexUBERON:000187092.42gold quality
lower esophagusUBERON:001347392.40gold quality
lower esophagus muscularis layerUBERON:003583392.40gold quality
neocortexUBERON:000195092.22gold quality
cerebral cortexUBERON:000095690.85gold quality
Ammon’s hornUBERON:000195490.03gold quality
temporal lobeUBERON:000187189.70gold quality
forebrainUBERON:000189089.18gold quality
brainUBERON:000095588.16gold quality
right hemisphere of cerebellumUBERON:001489087.32gold quality
popliteal arteryUBERON:000225087.22gold quality
tibial arteryUBERON:000761087.21gold quality
cerebellar hemisphereUBERON:000224586.63gold quality
saphenous veinUBERON:000731886.58gold quality
smooth muscle tissueUBERON:000113586.54gold quality
cerebellar cortexUBERON:000212986.53gold quality
superior frontal gyrusUBERON:000266186.00gold quality
mucosa of stomachUBERON:000119985.97gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

ExperimentMarker?Max mean expression
E-ANND-3yes4.99

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

  • Pnck induces ligand-independent EGFR degradation, and it may represent an attractive therapeutic target in EGFR-regulated oncogenesis. (PMID:18562482)
  • Pnck induces epidermal growth factor receptor degradation, most likely through perturbation of Hsp90 chaperone activity due to Hsp90 phosphorylation. Epidermal growth factor receptor degradation is coupled to proteasomal degradation of Pnck. (PMID:21325639)
  • the relationship between PNCK and prognosis in clear cell renal cell carcinoma (PMID:23634203)
  • Pnck may be a marker of Trastuzumab resistance and possibly a therapeutic target in breast cancer. (PMID:25773930)
  • Expression of Pregnancy Up-regulated Non-ubiquitous Calmodulin Kinase (PNCK) in Hepatocellular Carcinoma. (PMID:33099476)

Cross-species orthologs

2 orthologs

OrganismSymbolGene ID
mus_musculusPnckENSMUSG00000002012
rattus_norvegicusPnckENSRNOG00000058317

Paralogs (22): CAMKK1 (ENSG00000004660), CAMK1G (ENSG00000008118), CAMK2B (ENSG00000058404), CAMK2A (ENSG00000070808), MYLK2 (ENSG00000101306), CAMKK2 (ENSG00000110931), STK11 (ENSG00000118046), STK33 (ENSG00000130413), DCLK1 (ENSG00000133083), CAMK1 (ENSG00000134072), MYLK3 (ENSG00000140795), CAMK2D (ENSG00000145349), MYLK4 (ENSG00000145949), PSKH2 (ENSG00000147613), CAMK2G (ENSG00000148660), PHKG2 (ENSG00000156873), PSKH1 (ENSG00000159792), DCLK3 (ENSG00000163673), CAMKV (ENSG00000164076), PHKG1 (ENSG00000164776), DCLK2 (ENSG00000170390), CAMK1D (ENSG00000183049)

Protein

Protein identifiers

Calcium/calmodulin-dependent protein kinase type 1BQ6P2M8 (reviewed: Q6P2M8)

Alternative names: CaM kinase I beta, Pregnancy up-regulated non-ubiquitously-expressed CaM kinase

All UniProt accessions (9): Q6P2M8, C9J2B9, C9J8P0, C9JB09, C9JEC5, C9JJ18, F8WAQ5, F8WBU7, H7BZQ5

UniProt curated annotations — full annotation on UniProt →

Function. Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade. In vitro phosphorylates CREB1 and SYN1/synapsin I. Phosphorylates and activates CAMK1.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated by CAMKK1.

Activity regulation. Activated by Ca(2+)/calmodulin.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.

Isoforms (5)

UniProt IDNamesCanonical?
Q6P2M8-11yes
Q6P2M8-22
Q6P2M8-33
Q6P2M8-54
Q6P2M8-65

RefSeq proteins (8): NP_001034671, NP_001129212, NP_001353904, NP_001353905, NP_001353906, NP_001353907, NP_001353908, NP_001353909 (=MANE)

Domains & families (InterPro)

IDNameType
IPR000719Prot_kinase_domDomain
IPR008271Ser/Thr_kinase_ASActive_site
IPR011009Kinase-like_dom_sfHomologous_superfamily
IPR017441Protein_kinase_ATP_BSBinding_site
IPR042696CaMKI_beta_STKcDomain

Pfam: PF00069

Catalyzed reactions (Rhea), 2 shown:

  • L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
  • L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (13 total): splice variant 4, region of interest 2, binding site 2, chain 1, domain 1, sequence variant 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q6P2M8-F182.400.56

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 136 (proton acceptor)

Ligand- & substrate-binding residues (2): 21–29; 44

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 73 (showing top): AREB6_03, CAGGTCC_MIR492, CATRRAGC_UNKNOWN, DURCHDEWALD_SKIN_CARCINOGENESIS_DN, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_DN, GOMF_PROTEIN_KINASE_ACTIVITY, GOMF_KINASE_ACTIVITY, GOMF_CALCIUM_CALMODULIN_DEPENDENT_PROTEIN_KINASE_ACTIVITY, YOSHIMURA_MAPK8_TARGETS_UP, GOMF_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY, GOMF_ADENYL_NUCLEOTIDE_BINDING, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_PHOSPHORUS_CONTAINING_GROUPS, chrXq28, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_B, BAKKER_FOXO3_TARGETS_DN

GO Biological Process (2): signal transduction (GO:0007165), protein phosphorylation (GO:0006468)

GO Molecular Function (9): calcium/calmodulin-dependent protein kinase activity (GO:0004683), calmodulin binding (GO:0005516), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
protein kinase activity2
cell communication1
cellular process1
signaling1
regulation of cellular process1
cellular response to stimulus1
phosphorylation1
protein modification process1
protein serine/threonine kinase activity1
protein binding1
adenyl ribonucleotide binding1
purine ribonucleoside triphosphate binding1
nucleoside phosphate binding1
heterocyclic compound binding1
kinase activity1
phosphotransferase activity, alcohol group as acceptor1
catalytic activity, acting on a protein1
transferase activity, transferring phosphorus-containing groups1
catalytic activity1
intracellular membrane-bounded organelle1
intracellular anatomical structure1
cellular anatomical structure1

Protein interactions and networks

STRING

1714 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
PNCKIRAK1P51617533
PNCKNOMO3P69849507
PNCKNOMO2Q5JPE7507
PNCKNOMO1P78421505
PNCKFGF3P11487496
PNCKHAUS7Q99871463
PNCKCALM1P02593424
PNCKCALML3P27482423
PNCKCALML5Q9NZT1423
PNCKCAMK2AQ9UQM7422
PNCKKRT3P12035408
PNCKTEX28O15482401
PNCKDENRO43583397
PNCKCALML6Q8TD86386
PNCKCALML4Q96GE6386

IntAct

3 interactions, top by confidence:

ABTypeScore
PNCKPTPN11psi-mi:“MI:0915”(physical association)0.370
EPHA4PNCKpsi-mi:“MI:0915”(physical association)0.000

BioGRID (1): PNCK (Two-hybrid)

ESM2 similar proteins: A8X6H4, O70150, O75582, P10665, P11275, P11798, P18652, P18653, P18654, P28583, P51812, Q13557, Q14012, Q15349, Q2HJF7, Q38869, Q38871, Q38872, Q39016, Q42396, Q54CY9, Q54SJ5, Q5F3L1, Q5R4K3, Q5RCC4, Q5ZKI0, Q63450, Q63531, Q6DEH3, Q6GLS4, Q6P2M8, Q6PFQ0, Q6PHZ2, Q7TPS0, Q869W6, Q8BW96, Q8IU85, Q8RWL2, Q8VDF3, Q91YS8

Diamond homologs: A0A2I0BVG8, A0A509AFG4, A0A509AHB6, A0A509ALV6, A0A509AQE6, A0A5K1K8H0, A2XFF4, A8X6H4, B8BBT7, E9PT87, F4JBP3, O15865, O22932, O61267, O70150, O80673, P05986, P08414, P13234, P18654, P22216, P22517, P25323, P27466, P28582, P34101, P40376, P51812, P53681, P53684, P62343, P62344, P62345, P92958, P93759, Q00771, Q09170, Q0D715, Q0VD22, Q10KY3

SIGNOR signaling

1 interactions.

AEffectBMechanism
PNCKup-regulatesEIF4G3phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

63 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance31
Likely benign5
Benign2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1808 predictions. Top by Δscore:

VariantEffectΔscore
X:153670740:TGA:Tdonor_loss1.0000
X:153670741:GACC:Gdonor_loss1.0000
X:153670830:TC:Tacceptor_gain1.0000
X:153670830:TCC:Tacceptor_loss1.0000
X:153670831:CC:Cacceptor_gain1.0000
X:153670831:CCT:Cacceptor_loss1.0000
X:153670832:C:CCacceptor_gain1.0000
X:153670832:CTGG:Cacceptor_loss1.0000
X:153670914:TCA:Tdonor_loss1.0000
X:153670915:CACCA:Cdonor_loss1.0000
X:153670916:A:ACdonor_gain1.0000
X:153670916:ACCA:Adonor_loss1.0000
X:153670917:C:Adonor_loss1.0000
X:153670917:C:CCdonor_gain1.0000
X:153670917:CCAAA:Cdonor_gain1.0000
X:153670992:TTTGG:Tacceptor_gain1.0000
X:153670993:TTGG:Tacceptor_gain1.0000
X:153670994:TGG:Tacceptor_gain1.0000
X:153670995:GG:Gacceptor_gain1.0000
X:153670997:C:CCacceptor_gain1.0000
X:153670998:T:Cacceptor_loss1.0000
X:153671542:C:Adonor_gain1.0000
X:153671582:G:Cdonor_gain1.0000
X:153671592:AG:Adonor_gain1.0000
X:153672119:T:TAdonor_gain1.0000
X:153672124:A:ACdonor_gain1.0000
X:153672125:C:CCdonor_gain1.0000
X:153672125:CAGTT:Cdonor_gain1.0000
X:153672129:T:TAdonor_gain1.0000
X:153672561:CGCA:Cdonor_loss1.0000

AlphaMissense

2239 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
X:153671313:A:GW196R1.000
X:153671313:A:TW196R1.000
X:153671616:G:CD157E1.000
X:153671616:G:TD157E1.000
X:153671617:T:AD157V1.000
X:153671617:T:GD157A1.000
X:153671887:T:AD136V1.000
X:153671887:T:GD136A1.000
X:153672634:C:AK44N1.000
X:153672634:C:GK44N1.000
X:153670951:C:AR258M0.999
X:153671099:A:GW236R0.999
X:153671099:A:TW236R0.999
X:153671169:G:CF212L0.999
X:153671169:G:TF212L0.999
X:153671171:A:GF212L0.999
X:153671173:G:TP211H0.999
X:153671303:C:TG199D0.999
X:153671304:C:GG199R0.999
X:153671311:C:AW196C0.999
X:153671311:C:GW196C0.999
X:153671566:C:TG174E0.999
X:153671611:C:TG159E0.999
X:153671617:T:CD157G0.999
X:153671618:C:GD157H0.999
X:153671662:A:GL142P0.999
X:153671664:G:CN141K0.999
X:153671664:G:TN141K0.999
X:153671666:T:CN141D0.999
X:153671880:C:AK138N0.999

dbSNP variants (sampled 300 via entrez): RS1000329399 (X:153670074 C>T), RS1000445471 (X:153669894 G>T), RS1000513717 (X:153678393 A>C), RS1001304544 (X:153683400 A>C,G), RS1002218138 (X:153676224 A>G), RS1002316609 (X:153685413 C>T), RS1002592102 (X:153676744 A>T), RS1002814103 (X:153672500 A>C), RS1002976486 (X:153681346 G>A), RS1003255895 (X:153672048 G>A,T), RS1004507513 (X:153675075 G>T), RS1004733690 (X:153683972 T>C), RS1005106287 (X:153684427 C>T), RS1005287908 (X:153670486 G>A), RS1005391419 (X:153679788 T>C)

Disease associations

OMIM: gene MIM:300680 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3627592 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — CAMK1 family

ChEMBL bioactivities

11 potent at pChembl≥5 of 11 total, top 11 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
8.52IC503nMCHEMBL4635883
8.42IC503.78nMSTAUROSPORINE
8.30IC504.99nMSTAUROSPORINE
8.21IC506.12nMSTAUROSPORINE
7.96IC5011nMCHEMBL4640712
6.08IC50830nMCHEMBL5093741
6.00IC501000nMTP-030-1
6.00IC501000nMTP-030-2
6.00IC501000nMTP-030n
5.52IC503000nMCHEMBL4795714
5.00Kd1e+04nMCHEMBL4848254

PubChem BioAssay actives

8 with measured affinity, of 70 total; 6 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
2-[(3S)-3-aminopiperidin-1-yl]-4-[[2,6-di(propan-2-yl)-4-pyridinyl]amino]pyrimidine-5-carboxamide1668857: Inhibition of human CAMK1B using KKALRRQETVDAL as substrate in presence of [gamma-33P]-ATP by hotspot kinase assayic500.0030uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one1715431: Inhibition of human CAMK1B using KKALRRQETVDAL as substrate by [gamma-33P]-ATP assayic500.0038uM
2-[(3S)-3-aminopiperidin-1-yl]-4-[3,5-bis(2-cyanopropan-2-yl)anilino]pyrimidine-5-carboxamide1668857: Inhibition of human CAMK1B using KKALRRQETVDAL as substrate in presence of [gamma-33P]-ATP by hotspot kinase assayic500.0110uM
10,14-dimethyl-9-oxo-3-(trifluoromethyl)-4,5,10,13,14,19,21-heptazapentacyclo[15.5.2.12,5.012,16.020,23]pentacosa-1(22),2(25),3,12,15,17(24),18,20(23)-octaene-15-carbonitrile1823455: Inhibition of CAMK1B (unknown origin) at 1 uM by kinome scan methodic500.8300uM
1-pentyl-4-(2-phenylmethoxyphenyl)imidazol-2-amine;hydrochloride1734145: Inhibition of wild-type human CAMK1beta using KKALRRQETVDAL peptide as substrate in presence of Ca2+ calmodulin and [gamma-33P]-ATP by radiometric hotspot kinase assayic503.0000uM
N,N-dimethyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine1752106: Binding affinity to wild-type human partial length CAMK1B (W9 to A311 residues) expressed in mammalian expression system measured after 1 hr by competitive binding assaykd10.0000uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

ChemicalActions (top 5)PubMed papers
Valproic Acidincreases methylation, affects cotreatment, decreases expression3
trichostatin Aaffects cotreatment, decreases expression2
Air Pollutantsincreases abundance, increases expression2
Phenylmercuric Acetateaffects cotreatment, decreases expression2
Smokedecreases expression, increases abundance, increases expression2
methylmercuric chloridedecreases expression1
bisphenol Aaffects expression1
sulforaphaneincreases expression1
aflatoxin B2increases methylation1
S-(1,2-dichlorovinyl)cysteineaffects cotreatment, decreases expression1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, decreases expression1
nutlin 3increases expression, affects cotreatment1
dorsomorphindecreases expression, affects cotreatment1
licochalcone Bincreases expression1
Decitabineaffects expression1
Benzo(a)pyrenedecreases methylation, increases methylation1
Cisplatinaffects expression1
Dactinomycinaffects cotreatment, increases expression1
Diethylhexyl Phthalatedecreases expression1
Leadaffects expression1
Lipopolysaccharidesaffects cotreatment, decreases expression1
Oxygenincreases expression1
Phthalic Acidsincreases methylation1
Testosteroneincreases expression1
Tetrachlorodibenzodioxinincreases activity, affects reaction1
Aflatoxin B1increases methylation1
Cadmium Chloridedecreases expression1
Acrylamidedecreases expression1
Particulate Matterincreases abundance, increases expression1

ChEMBL screening assays

82 unique, capped per target: 82 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL3632282BindingInhibition of CAMK1beta (unknown origin) at 10 uM after 120 mins P33 radiolabeled kinase activity assayCrystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

CellosaurusNameCategorySex
CVCL_TE75HAP1 PNCK (-) 1Cancer cell lineMale
CVCL_TE76HAP1 PNCK (-) 2Cancer cell lineMale

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.