Reactome | p-V600K BRAF [plasma membrane]

p-V600K BRAF

Stable Identifier

R-HSA-8936651

Type

Protein [EntityWithAccessionedSequence]

Species

Homo sapiens

Compartment

plasma membrane

Synonyms

B-RAF

Locations in the PathwayBrowser

Expand all

Disease (Homo sapiens)

- Diseases of signal transduction (Homo sapiens)
  - Oncogenic MAPK signaling (Homo sapiens)
    - Signaling by moderate kinase activity BRAF mutants (Homo sapiens)
      - Activated MAP2Ks phosphorylate MAPKs downstream of moderate kinase activity BRAF mutants (Homo sapiens)
        
        RAS:GTP:moderate kinase activity p-RAF:p-2S MAP2Ks:MAPKs:scaffold proteins [plasma membrane] (Homo sapiens)
        
        RAS:GTP:moderate kinase activity BRAF mutants:p-RAF:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated RAFs:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants [plasma membrane] (Homo sapiens)
        
        p-V600K BRAF [plasma membrane] (Homo sapiens)
        
        RAS:GTP:moderate kinase activity p-RAF:p-2S MAP2Ks:p-T,Y MAPKs:scaffold proteins [plasma membrane] (Homo sapiens)
        
        RAS:GTP:moderate kinase activity BRAF mutants:p-RAF:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated RAFs:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants [plasma membrane] (Homo sapiens)
        
        p-V600K BRAF [plasma membrane] (Homo sapiens)
      - Dissociation of moderate activity BRAF complexes (Homo sapiens)
        
        RAS:GTP:moderate kinase activity BRAF mutants:p-RAF:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated RAFs:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants [plasma membrane] (Homo sapiens)
        
        p-V600K BRAF [plasma membrane] (Homo sapiens)
        
        RAS:GTP:moderate kinase activity p-RAF:p-2S MAP2Ks:p-T,Y MAPKs:scaffold proteins [plasma membrane] (Homo sapiens)
        
        RAS:GTP:moderate kinase activity BRAF mutants:p-RAF:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated RAFs:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants [plasma membrane] (Homo sapiens)
        
        p-V600K BRAF [plasma membrane] (Homo sapiens)
      - RAF is phosphorylated downstream of moderate kinase activity BRAF mutants (Homo sapiens)
        
        RAS:GTP:moderate kinase activity BRAF mutants:p-RAF:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated RAFs:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants [plasma membrane] (Homo sapiens)
        
        p-V600K BRAF [plasma membrane] (Homo sapiens)
      - RAS:GTP:moderate kinase activity p-RAF complexes bind MAP2Ks and MAPKs (Homo sapiens)
        
        RAS:GTP:moderate kinase activity BRAF mutants:p-RAF:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated RAFs:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants [plasma membrane] (Homo sapiens)
        
        p-V600K BRAF [plasma membrane] (Homo sapiens)
        
        RAS:GTP:moderate kinase activity p-RAF:MAP2Ks:MAPKs:scaffold proteins [plasma membrane] (Homo sapiens)
        
        RAS:GTP:moderate kinase activity BRAF mutants:p-RAF:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated RAFs:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants [plasma membrane] (Homo sapiens)
        
        p-V600K BRAF [plasma membrane] (Homo sapiens)
      - RAS:GTP:moderate kinase activity p-RAF complexes phosphorylate MAP2Ks (Homo sapiens)
        
        RAS:GTP:moderate kinase activity p-RAF:MAP2Ks:MAPKs:scaffold proteins [plasma membrane] (Homo sapiens)
        
        RAS:GTP:moderate kinase activity BRAF mutants:p-RAF:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated RAFs:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants [plasma membrane] (Homo sapiens)
        
        p-V600K BRAF [plasma membrane] (Homo sapiens)
        
        RAS:GTP:moderate kinase activity p-RAF:p-2S MAP2Ks:MAPKs:scaffold proteins [plasma membrane] (Homo sapiens)
        
        RAS:GTP:moderate kinase activity BRAF mutants:p-RAF:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated RAFs:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants:YWHAB [plasma membrane] (Homo sapiens)
        
        phosphorylated moderate kinase activity BRAF mutants [plasma membrane] (Homo sapiens)
        
        p-V600K BRAF [plasma membrane] (Homo sapiens)

Literature References

PubMed ID	Title	Journal	Year
15035987	Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF	Cell	2004
12068308	Mutations of the BRAF gene in human cancer	Nature	2002

External Reference Information

External Reference

UniProt:P15056 BRAF

Gene Names

BRAF, BRAF1, RAFB1

Chain

initiator methionine:1, chain:2-766

Reference Genes

BioGPS Gene:673 BRAF

COSMIC (genes):BRAF BRAF

CTD Gene:673 BRAF

dbSNP Gene:673 BRAF

ENSEMBL:ENSG00000157764 BRAF

HGNC:1097 BRAF

KEGG Gene (Homo sapiens):hsa:673 BRAF

Monarch:673 BRAF

NCBI Gene:673 BRAF

OMIM:164757 BRAF

UCSC:P15056 BRAF

Reference Transcript

RefSeq:NM_004333.4 BRAF

Other Identifiers

11732491_s_at

1328

1654_at

17063631

1UWH

1UWJ

206044_s_at

2FB8

2L05

3076367

3076368

3076370

3076372

3076374

3076375

3076380

3076381

3076382

3076383

3076384

3076386

3076388

3076392

3076393

3076396

3076399

3076414

3076416

3076439

3076440

3076441

3982166

3982173

3C4C

3D4Q

3IDP

3II5

3NY5

3OG7

3PPJ

3PPK

3PRF

3PRI

3PSB

3PSD

3Q4C

3Q96

3SKC

3TV4

3TV6

40306_at

4552

4CQE

4DBN

4E26

4E4X

4EHE

4EHG

4FC0

4FK3

4G9C

4G9R

4H58

4JVG

4KSP

4KSQ

4MBJ

4MNE

4MNF

4PP7

4R5Y

4RZV

4RZW

4WO5

4XV1

4XV2

4XV3

4XV9

4YHT

5C9C

5CSW

5CSX

5CT7

5FD2

5HI2

5HID

5HIE

5ITA

5J17

5J18

5J2R

5JRQ

5JSM

5JT2

673

71048

8143417

A_23_P42935

BRAF

BRAF-201

CAB004552

CCDS5863

ENSG00000157764

ENSP00000288602

ENST00000288602

EntrezGene:673

g4757867_3p_a_at

GE58163

GO:0000165

GO:0000166

GO:0000186

GO:0002318

GO:0004672

GO:0004674

GO:0004709

GO:0005057

GO:0005509

GO:0005515

GO:0005524

GO:0005622

GO:0005634

GO:0005737

GO:0005739

GO:0005829

GO:0005886

GO:0006468

GO:0007165

GO:0008542

GO:0009887

GO:0009968

GO:0010628

GO:0010764

GO:0015758

GO:0016020

GO:0016301

GO:0016310

GO:0016740

GO:0030154

GO:0030878

GO:0031434

GO:0033138

GO:0035019

GO:0035556

GO:0035690

GO:0042127

GO:0042802

GO:0043005

GO:0043066

GO:0043231

GO:0043367

GO:0043368

GO:0043369

GO:0043434

GO:0043524

GO:0044297

GO:0045580

GO:0046632

GO:0046872

GO:0046982

GO:0048538

GO:0048679

GO:0048680

GO:0050772

GO:0050852

GO:0051291

GO:0051496

GO:0051591

GO:0060291

GO:0060323

GO:0060324

GO:0070374

GO:0071277

GO:0090150

GO:1900026

GO:1990090

GO:2000301

GO:2000352

HGNC:1097

HPA001328

HPA071048

ILMN_1652472

LRG_299

LRG_299t1

M95712_at

MIM:115150

MIM:163950

MIM:164757

MIM:211980

MIM:613706

MIM:613707

NM_004333

NP_001341538

NP_004324

PF00130

PF02196

PF07714

PH_hs_0027912

PR00008

SM00109

SM00220

SM00455

TC07001927.hg

uc003vwc.5

UPI000013DF26

XM_005250045

XM_017012558

XM_017012559

XP_016868047

XP_016868048

XR_001744857

XR_001744858

Participant Of

hasMember

phosphorylated moderate kinase activity BRAF mutants [plasma membrane]

Other forms of this molecule

BRAF-MACF1fusion [cytosol]

p-BRAF-MACF1 fusion [cytosol]

D594N BRAF [cytosol]

G596R BRAF [cytosol]

D594V BRAF [cytosol]

G466E BRAF [cytosol]

D594G BRAF [cytosol]

F595L BRAF [cytosol]

L597V BRAF [cytosol]

G464E BRAF [cytosol]

E586K BRAF [cytosol]

V600K BRAF [cytosol]

p-L597V BRAF [plasma membrane]

p-G464E BRAF [plasma membrane]

p-F595L BRAF [plasma membrane]

p-E586K BRAF [plasma membrane]

BRAF 599dupT [cytosol]

G469A BRAF [cytosol]

V600E BRAF [cytosol]

V600E BRAF V169_M438del [cytosol]

V600E BRAF V47_D380del [cytosol]

V600E BRAF V47_M438del [cytosol]

V600E BRAF V169_D380del [cytosol]

p-S445,S729-BRAF [plasma membrane]

p-S,T-BRAF [cytosol]

BRAF [endosome]

p-S338-BRAF [plasma membrane]

BRAF [plasma membrane]

hyperphosphorylated BRAF [plasma membrane]

p-S365,S445,S729 BRAF [cytosol]

BRAF [cytosol]

p-S445,T599,S602,S729 BRAF [plasma membrane]

p-S445,S729-BRAF [cytosol]

p-S445,T599,S602,S729 BRAF [cytosol]

Modified Residues

Name

O-phospho-L-serine at 729

Coordinate

729

PsiMod Name

O-phospho-L-serine [MOD:00046]

PsiMod Definition

A protein modification that effectively converts an L-serine residue to O-phospho-L-serine.

Name

O-phospho-L-serine at 445

Coordinate

445

PsiMod Name

O-phospho-L-serine [MOD:00046]

PsiMod Definition

A protein modification that effectively converts an L-serine residue to O-phospho-L-serine.

Name

O-phospho-L-threonine at 599

Coordinate

599

PsiMod Name

O-phospho-L-threonine [MOD:00047]

PsiMod Definition

A protein modification that effectively converts an L-threonine residue to O-phospho-L-threonine.

Name

O-phospho-L-serine at 602

Coordinate

602

PsiMod Name

O-phospho-L-serine [MOD:00046]

PsiMod Definition

A protein modification that effectively converts an L-serine residue to O-phospho-L-serine.

Name

L-valine 600 replaced with L-lysine

Coordinate

600

PsiMod HEY

L-valine removal [MOD:01650]

A protein modification that effectively removes or replaces an L-valine.

L-lysine residue [MOD:00021]

A protein modification that effectively converts a source amino acid residue to L-lysine.

Disease

Name	Identifier	Synonyms
melanoma	1909	Naevocarcinoma, melanoma, melanoma, malignant melanoma, morphology (morphologic abnormality), malignant melanoma NOS (morphologic abnormality), malignant melanoma (disorder), malignant melanoma, malignant melanoma, malignant melanoma, malignant melanoma

Cross References

RefSeq

NP_004324.2

Brenda

2.7.11.1

ZINC - World Drugs

BRAF_HUMAN

ZINC - FDA approved

BRAF_HUMAN

ZINC - Substances

BRAF_HUMAN

ZINC target

P15056

ZINC - Biogenic

BRAF_HUMAN

PRO

P15056

PDB

3PSB, 5CSX, 3PSD, 5CT7, 3Q4C, 3Q96, 3SKC, 5FD2, 4XV9, 4YHT, 3PPJ, 5C9C, 3PPK, 3PRF, 5CSW, 3PRI, 3D4Q, 5VAM, 4WO5, 6B8U, 4XV1, 3IDP, 3II5, 4XV2, 4XV3, 3NY5, 3OG7, 1UWH, 5J2R, 4PP7, 4R5Y, 1UWJ, 5JRQ, 5JSM, 2FB8, 4RZV, 2L05, 5JT2, 3C4C, 5VAL, 4RZW, 4KSQ, 5J18, 4MBJ, 4MNE, 4MNF, 4FK3, 4G9C, 4G9R, 4E26, 4DBN, 5HID, 4CQE, 3TV6, 5HI2, 3TV4, 5ITA, 4FC0, 4EHG, 4EHE, 4E4X, 5HIE, 4KSP, 4JVG, 5J17, 4H58

ZINC - Metabolites

BRAF_HUMAN

GeneCards

P15056

DOCK Blaster

3D4Q, 3TV6, 5ITA, 4XV9, 3PSB, 3Q4C, 3PSD, 3TV4, 3II5, 5HIE, 5HID, 3PRF, 3PRI, 4CQE, 4XV3, 4KSP, 4KSQ, 3PPK, 3PPJ, 4R5Y, 5JSM, 4E4X, 5JT2, 4MNE, 4G9R, 4MNF, 5JRQ, 5HI2, 4EHG, 4G9C, 4EHE, 3NY5, 3IDP, 4RZV, 4RZW, 3C4C, 4XV2, 4E26, 4FK3, 4WO5, 4DBN, 4PP7, 4H58, 3SKC, 3Q96, 2FB8, 4FC0, 5FD2, 5CSW, 5CSX, 5CT7, 3OG7, 4YHT, 4XV1, 5C9C, 4MBJ, 4JVG, 1UWJ, 1UWH

COSMIC (mutations)

COSM473

Orphanet

15376

ZINC - Predictions - Purchasable

BRAF_HUMAN

HMDB Protein

HMDBP02597

Interactors (16)

Accession	#Entities	Entities	Confidence Score	Evidence (IntAct)
UniProt:Q02750 MAP2K1	7	MAP2K1(2-8) [cytosol] (R-HSA-5211342) MAP2K1(9-393) [cytosol] (R-HSA-5211353) p-S,218, S222,T292 MAP2K1 [cytosol] (R-HSA-5674490) p-T286,T292-MAP2K1 [cytosol] (R-HSA-112374) p-S218,S222,T286,T292-MAP2K1 [cytosol] (R-HSA-112339) MAP2K1 [cytosol] (R-HSA-59502) p-S218,S222-MAP2K1 [cytosol] (R-HSA-109837)	0.976	58
UniProt:P04049 RAF1	11	p-S338-RAF1 [cytosol] (R-HSA-5624469) p-S338,Y340,Y341-RAF1 [cytosol] (R-HSA-5624465) RAF1 [cytosol] (R-HSA-167205) p-S338-RAF1 [plasma membrane] (R-HSA-444236) p-S621-RAF1 [plasma membrane] (R-HSA-206222) hyperphosphorylated RAF1 [plasma membrane] (R-HSA-5675193) p-Y341,T491,S494,S621 RAF1 [plasma membrane] (R-HSA-5675420) p-S259,S621-RAF1 [cytosol] (R-HSA-109786) p-S621-RAF1 [cytosol] (R-HSA-206028) p-S338,Y341,T491,S494,S621 RAF1 [plasma membrane] (R-HSA-5672665) p-S338,Y341,T491,S494,S621 RAF1 [cytosol] (R-HSA-5672664)	0.957	55
UniProt:P15056 BRAF	35	p-BRAF-MACF1 fusion [cytosol] (R-HSA-6802536) BRAF-MACF1fusion [cytosol] (R-HSA-6802402) D594N BRAF [cytosol] (R-HSA-6802299) G596R BRAF [cytosol] (R-HSA-6802385) D594V BRAF [cytosol] (R-HSA-6802305) G466E BRAF [cytosol] (R-HSA-6802374) D594G BRAF [cytosol] (R-HSA-6802295) F595L BRAF [cytosol] (R-HSA-6802316) L597V BRAF [cytosol] (R-HSA-6802397) G464E BRAF [cytosol] (R-HSA-6802369) E586K BRAF [cytosol] (R-HSA-6802308) V600K BRAF [cytosol] (R-HSA-6802502) p-L597V BRAF [plasma membrane] (R-HSA-8936647) p-G464E BRAF [plasma membrane] (R-HSA-8936645) p-F595L BRAF [plasma membrane] (R-HSA-8936641) p-E586K BRAF [plasma membrane] (R-HSA-8936639) p-V600K BRAF [plasma membrane] (R-HSA-8936651) BRAF 599dupT [cytosol] (R-HSA-6802281) G469A BRAF [cytosol] (R-HSA-6802381) V600E BRAF [cytosol] (R-HSA-6802498) V600E BRAF V169_M438del [cytosol] (R-HSA-6802489) V600E BRAF V47_D380del [cytosol] (R-HSA-6802491) V600E BRAF V47_M438del [cytosol] (R-HSA-6802495) V600E BRAF V169_D380del [cytosol] (R-HSA-6802486) p-S445,S729-BRAF [plasma membrane] (R-HSA-8933622) p-S,T-BRAF [cytosol] (R-HSA-169856) BRAF [endosome] (R-HSA-190063) p-S338-BRAF [plasma membrane] (R-HSA-1063700) BRAF [plasma membrane] (R-HSA-934547) hyperphosphorylated BRAF [plasma membrane] (R-HSA-5675199) p-S365,S445,S729 BRAF [cytosol] (R-HSA-5672667) BRAF [cytosol] (R-HSA-167224) p-S445,T599,S602,S729 BRAF [plasma membrane] (R-HSA-5672679) p-S445,S729-BRAF [cytosol] (R-HSA-5672673) p-S445,T599,S602,S729 BRAF [cytosol] (R-HSA-5672676)	0.907	13
UniProt:P63104 YWHAZ	2	YWHAZ [nucleoplasm] (R-HSA-450469) YWHAZ [cytosol] (R-HSA-206099)	0.822	6
UniProt:P31946 YWHAB	2	YWHAB [endosome] (R-HSA-190058) YWHAB [cytosol] (R-HSA-48888)	0.763	5
UniProt:P01112 HRAS	8	Q61L HRAS [plasma membrane] (R-HSA-6802452) Q61R HRAS [plasma membrane] (R-HSA-6802458) Q61K HRAS [plasma membrane] (R-HSA-6802442) G12V HRAS [plasma membrane] (R-HSA-6802350) G13R HRAS [plasma membrane] (R-HSA-6802368) G12S HRAS [plasma membrane] (R-HSA-6802343) HRAS [cytosol] (R-HSA-205771) HRAS [plasma membrane] (R-HSA-62717)	0.719	4
UniProt:P61981 YWHAG	1	YWHAG [cytosol] (R-HSA-380312)	0.688	3
UniProt:P27348 YWHAQ	1	YWHAQ [cytosol] (R-HSA-1445116)	0.688	3
UniProt:P10398 ARAF	4	p-S299,S302,T452,T455,S576 ARAF [plasma membrane] (R-HSA-5672648) p-S299,S302,T452,T455,S576 ARAF [cytosol] (R-HSA-5672646) p-S576 ARAF [cytosol] (R-HSA-5672681) p-S214,S576 ARAF [cytosol] (R-HSA-5672639)	0.669	3
UniProt:P36507 MAP2K2	5	MAP2K2(11-400) [cytosol] (R-HSA-5211337) MAP2K2(1-10) [cytosol] (R-HSA-5211334) MAP2K2 [cytosol] (R-HSA-59504) p-S222,S226-MAP2K2 [cytosol] (R-HSA-169292) p-S,T-MAP2K2 [cytosol] (R-HSA-109848)	0.669	6
UniProt:Q13233 MAP3K1	2	p-Y1400,Y1412-MAP3K1 [cytosol] (R-HSA-2685607) MAP3K1 [cytosol] (R-HSA-166866)	0.609	2
UniProt:P01111 NRAS	8	Q61R NRAS [plasma membrane] (R-HSA-6802461) G13D NRAS [plasma membrane] (R-HSA-6802363) Q61L NRAS [plasma membrane] (R-HSA-6802455) G12S NRAS [plasma membrane] (R-HSA-6802347) Q61K NRAS [plasma membrane] (R-HSA-6802446) G12D NRAS [plasma membrane] (R-HSA-6802339) NRAS [tertiary granule membrane] (R-HSA-6800190) NRAS [plasma membrane] (R-HSA-62725)	0.591	3
UniProt:P08238 HSP90AB1	5	HSP90AB1 [extracellular region] (R-HSA-6806463) HSP90AB1 [secretory granule lumen] (R-HSA-6801477) HSP90AB1 [ficolin-1-rich granule lumen] (R-HSA-6801491) HSP90AB1 [cytosol] (R-HSA-419617) HSP90AB1 [nucleoplasm] (R-HSA-5082399)	0.564	2
UniProt:P46940 IQGAP1	3	IQGAP1 [secretory granule membrane] (R-HSA-6804803) IQGAP1 [cytosol] (R-HSA-5626371) IQGAP1 [plasma membrane] (R-HSA-381681)	0.544	4
UniProt:Q61097	5	phospho-p-S311,S406 KSR1 [cytosol] (R-MMU-5672654) KSR1 [cytosol] (R-MMU-5672587) phospho-p-S311 KSR1 [cytosol] (R-MMU-5672652) phospho-p-S311,Y552 KSR1 [plasma membrane] (R-MMU-5672659) phospho-p-S311,Y552 KSR1 [cytosol] (R-MMU-5672656)	0.499	3
UniProt:Q99N57	11	phospho-p-S338-RAF1 [cytosol] (R-MMU-5624469) phospho-p-S338,Y340,Y341-RAF1 [cytosol] (R-MMU-5624465) RAF1 [cytosol] (R-MMU-167205) phospho-p-S338-RAF1 [plasma membrane] (R-MMU-444236) phospho-p-S621-RAF1 [plasma membrane] (R-MMU-206222) phospho-hyperphosphorylated RAF1 [plasma membrane] (R-MMU-5675193) phospho-p-Y341,T491,S494,S621 RAF1 [plasma membrane] (R-MMU-5675420) phospho-p-S259,S621-RAF1 [cytosol] (R-MMU-109786) phospho-p-S621-RAF1 [cytosol] (R-MMU-206028) phospho-p-S338,Y341,T491,S494,S621 RAF1 [plasma membrane] (R-MMU-5672665) phospho-p-S338,Y341,T491,S494,S621 RAF1 [cytosol] (R-MMU-5672664)	0.499	3