O15123 (ANGP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Angiopoietin-2
Short name=ANG-2

Gene names

Name:

ANGPT2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	496 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Binds to TEK/TIE2, competing for the ANGPT1 binding site, and modulating ANGPT1 signaling. Can induce tyrosine phosphorylation of TEK/TIE2 in the absence of ANGPT1. In the absence of angiogenic inducers, such as VEGF, ANGPT2-mediated loosening of cell-matrix contacts may induce endothelial cell apoptosis with consequent vascular regression. In concert with VEGF, it may facilitate endothelial cell migration and proliferation, thus serving as a permissive angiogenic signal. Ref.1 Ref.9 Ref.10 Ref.11
Subunit structure	Interacts with TEK/TIE2, competing for the same binding site as ANGPT1. Ref.1 Ref.8 Ref.9 Ref.11
Subcellular location	Secreted.
Domain	The Fibrinogen C-terminal domain mediates interaction with the TEK/TIE2 receptor.
Sequence similarities	Contains 1 fibrinogen C-terminal domain.

Ontologies

Keywords
Biological process	Angiogenesis Differentiation
Cellular component	Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Coiled coil Signal
Ligand	Calcium Metal-binding
Molecular function	Developmental protein
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	Tie receptor signaling pathway Inferred from direct assay. Source: UniProtKB angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW blood coagulation Traceable author statement. Source: Reactome leukocyte migration Traceable author statement. Source: Reactome negative regulation of blood vessel endothelial cell migration Inferred from direct assay. Source: UniProtKB negative regulation of positive chemotaxis Inferred from direct assay. Source: UniProtKB
Cellular component	extracellular space Inferred from direct assay. Source: UniProtKB
Molecular function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW receptor tyrosine kinase binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
TEK	Q02763	4	EBI-2912111,EBI-2257090

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O15123-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O15123-2)

The sequence of this isoform differs from the canonical sequence as follows:
     97-148: Missing.

Isoform 3 (identifier: O15123-3)

The sequence of this isoform differs from the canonical sequence as follows:
     268-268: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Potential

Chain

19 – 496

478

Angiopoietin-2

PRO_0000009113

Regions

Domain

275 – 495

221

Fibrinogen C-terminal

Coiled coil

166 – 248

83

Potential

Sites

Metal binding

429

1

Calcium

Metal binding

431

1

Calcium

Metal binding

433

1

Calcium; via carbonyl oxygen

Metal binding

435

1

Calcium; via carbonyl oxygen

Amino acid modifications

Glycosylation

89

1

N-linked (GlcNAc...) Potential

Glycosylation

119

1

N-linked (GlcNAc...) Potential

Glycosylation

133

1

N-linked (GlcNAc...) Potential

Glycosylation

151

1

N-linked (GlcNAc...) Potential

Glycosylation

240

1

N-linked (GlcNAc...) Potential

Glycosylation

304

1

N-linked (GlcNAc...) Potential

Disulfide bond

284 ↔ 313

Ref.13 Ref.14

Disulfide bond

433 ↔ 435

Ref.13 Ref.14

Disulfide bond

437 ↔ 450

Ref.13 Ref.14

Natural variations

Alternative sequence

97 – 148

52

Missing in isoform 2.

VSP_001540

Alternative sequence

268

1

Missing in isoform 3.

VSP_040096

Natural variant

333

1

V → I.
Corresponds to variant rs7813215 [ dbSNP | Ensembl ].

VAR_049069

Secondary structure

1

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496

Helix Strand Turn

Details...

Helix

284 – 288

5

Turn

289 – 291

3

Beta strand

296 – 301

6

Beta strand

308 – 314

7

Beta strand

322 – 331

10

Helix

339 – 344

6

Beta strand

351 – 353

3

Helix

357 – 366

10

Beta strand

369 – 376

8

Beta strand

382 – 392

11

Helix

395 – 397

3

Beta strand

401 – 410

10

Beta strand

431 – 435

5

Helix

437 – 441

5

Beta strand

448 – 450

3

Beta strand

452 – 454

3

Helix

475 – 478

4

Beta strand

485 – 493

9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: 5642A58847A7385C	FASTA	496	56,919
	10 20 30 40 50 60 MWQIVFFTLS CDLVLAAAYN NFRKSMDSIG KKQYQVQHGS CSYTFLLPEM DNCRSSSSPY 70 80 90 100 110 120 VSNAVQRDAP LEYDDSVQRL QVLENIMENN TQWLMKLENY IQDNMKKEMV EIQQNAVQNQ 130 140 150 160 170 180 TAVMIEIGTN LLNQTAEQTR KLTDVEAQVL NQTTRLELQL LEHSLSTNKL EKQILDQTSE 190 200 210 220 230 240 INKLQDKNSF LEKKVLAMED KHIIQLQSIK EEKDQLQVLV SKQNSIIEEL EKKIVTATVN 250 260 270 280 290 300 NSVLQKQQHD LMETVNNLLT MMSTSNSAKD PTVAKEEQIS FRDCAEVFKS GHTTNGIYTL 310 320 330 340 350 360 TFPNSTEEIK AYCDMEAGGG GWTIIQRRED GSVDFQRTWK EYKVGFGNPS GEYWLGNEFV 370 380 390 400 410 420 SQLTNQQRYV LKIHLKDWEG NEAYSLYEHF YLSSEELNYR IHLKGLTGTA GKISSISQPG 430 440 450 460 470 480 NDFSTKDGDN DKCICKCSQM LTGGWWFDAC GPSNLNGMYY PQRQNTNKFN GIKWYYWKGS 490 GYSLKATTMM IRPADF
	Isoform 2 [UniParc]. Checksum: E512409CE73987A1	FASTA	444	50,958
	10 20 30 40 50 60 MWQIVFFTLS CDLVLAAAYN NFRKSMDSIG KKQYQVQHGS CSYTFLLPEM DNCRSSSSPY 70 80 90 100 110 120 VSNAVQRDAP LEYDDSVQRL QVLENIMENN TQWLMKVLNQ TTRLELQLLE HSLSTNKLEK 130 140 150 160 170 180 QILDQTSEIN KLQDKNSFLE KKVLAMEDKH IIQLQSIKEE KDQLQVLVSK QNSIIEELEK 190 200 210 220 230 240 KIVTATVNNS VLQKQQHDLM ETVNNLLTMM STSNSAKDPT VAKEEQISFR DCAEVFKSGH 250 260 270 280 290 300 TTNGIYTLTF PNSTEEIKAY CDMEAGGGGW TIIQRREDGS VDFQRTWKEY KVGFGNPSGE 310 320 330 340 350 360 YWLGNEFVSQ LTNQQRYVLK IHLKDWEGNE AYSLYEHFYL SSEELNYRIH LKGLTGTAGK 370 380 390 400 410 420 ISSISQPGND FSTKDGDNDK CICKCSQMLT GGWWFDACGP SNLNGMYYPQ RQNTNKFNGI 430 440 KWYYWKGSGY SLKATTMMIR PADF
	Isoform 3 [UniParc]. Checksum: EBFAC35ABF1F08F6	FASTA	495	56,848
	10 20 30 40 50 60 MWQIVFFTLS CDLVLAAAYN NFRKSMDSIG KKQYQVQHGS CSYTFLLPEM DNCRSSSSPY 70 80 90 100 110 120 VSNAVQRDAP LEYDDSVQRL QVLENIMENN TQWLMKLENY IQDNMKKEMV EIQQNAVQNQ 130 140 150 160 170 180 TAVMIEIGTN LLNQTAEQTR KLTDVEAQVL NQTTRLELQL LEHSLSTNKL EKQILDQTSE 190 200 210 220 230 240 INKLQDKNSF LEKKVLAMED KHIIQLQSIK EEKDQLQVLV SKQNSIIEEL EKKIVTATVN 250 260 270 280 290 300 NSVLQKQQHD LMETVNNLLT MMSTSNSKDP TVAKEEQISF RDCAEVFKSG HTTNGIYTLT 310 320 330 340 350 360 FPNSTEEIKA YCDMEAGGGG WTIIQRREDG SVDFQRTWKE YKVGFGNPSG EYWLGNEFVS 370 380 390 400 410 420 QLTNQQRYVL KIHLKDWEGN EAYSLYEHFY LSSEELNYRI HLKGLTGTAG KISSISQPGN 430 440 450 460 470 480 DFSTKDGDND KCICKCSQML TGGWWFDACG PSNLNGMYYP QRQNTNKFNG IKWYYWKGSG 490 YSLKATTMMI RPADF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis." Maisonpierre P.C., Suri C., Jones P.F., Bartunkova S., Wiegand S.J., Radziejewski C., Compton D.L., McClain J., Aldrich T.H., Papadopoulos N., Daly T.J., Davis S., Sato T.N., Yancopoulos G.D. Science 277:55-60(1997) [PubMed: 9204896] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH TEK/TIE2, FUNCTION. Tissue: Lung.
[2]	"Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma." Tanaka S., Mori M., Sakamoto Y., Makuuchi M., Sugimachi K., Wands J.R. J. Clin. Invest. 103:341-345(1999) [PubMed: 9927494] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
[3]	"Characterization and expression of a novel alternatively spliced human angiopoietin-2." Kim I., Kim J.-H., Ryu Y.S., Jung S.H., Nah J.J., Koh G.Y. J. Biol. Chem. 275:18550-18556(2000) [PubMed: 10766762] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Umbilical vein endothelial cell.
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Substantia nigra.
[5]	"DNA sequence and analysis of human chromosome 8." Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., Asakawa T. , Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N., Lander E.S. Nature 439:331-335(2006) [PubMed: 16421571] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). Tissue: Colon.
[8]	"Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats." Fiedler U., Krissl T., Koidl S., Weiss C., Koblizek T., Deutsch U., Martiny-Baron G., Marme D., Augustin H.G. J. Biol. Chem. 278:1721-1727(2003) [PubMed: 12427764] [Abstract] Cited for: INTERACTION WITH TEK/TIE2.
[9]	"Biological characterization of angiopoietin-3 and angiopoietin-4." Lee H.J., Cho C.H., Hwang S.J., Choi H.H., Kim K.T., Ahn S.Y., Kim J.H., Oh J.L., Lee G.M., Koh G.Y. FASEB J. 18:1200-1208(2004) [PubMed: 15284220] [Abstract] Cited for: FUNCTION IN REGULATION OF ANGIOGENESIS; CELL SURVIVAL; CELL MIGRATION AND ACTIVATION OF AKT1, INTERACTION WITH TEK/TIE2.
[10]	"Tyrosine phosphatase beta regulates angiopoietin-Tie2 signaling in human endothelial cells." Yacyshyn O.K., Lai P.F.H., Forse K., Teichert-Kuliszewska K., Jurasz P., Stewart D.J. Angiogenesis 12:25-33(2009) [PubMed: 19116766] [Abstract] Cited for: FUNCTION.
[11]	"Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium." Yuan H.T., Khankin E.V., Karumanchi S.A., Parikh S.M. Mol. Cell. Biol. 29:2011-2022(2009) [PubMed: 19223473] [Abstract] Cited for: FUNCTION, INTERACTION WITH TEK/TIE2.
[12]	"Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system." Augustin H.G., Koh G.Y., Thurston G., Alitalo K. Nat. Rev. Mol. Cell Biol. 10:165-177(2009) [PubMed: 19234476] [Abstract] Cited for: REVIEW.
[13]	"Structure of the angiopoietin-2 receptor binding domain and identification of surfaces involved in Tie2 recognition." Barton W.A., Tzvetkova D., Nikolov D.B. Structure 13:825-832(2005) [PubMed: 15893672] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 281-496, DISULFIDE BONDS, CALCIUM-BINDING SITES.
[14]	"Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex." Barton W.A., Tzvetkova-Robev D., Miranda E.P., Kolev M.V., Rajashankar K.R., Himanen J.P., Nikolov D.B. Nat. Struct. Mol. Biol. 13:524-532(2006) [PubMed: 16732286] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.7 ANGSTROMS) OF 281-495 IN COMPLEX WITH TEK, DISULFIDE BONDS, CALCIUM-BINDING SITES.
+	Additional computationally mapped references.

Web resources

Wikipedia

Angiopoietin entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF004327 mRNA. Translation: AAB63190.1.
AB009865 mRNA. Translation: BAA95590.1.
AF187858 mRNA. Translation: AAF76526.1.
AK290070 mRNA. Translation: BAF82759.1.
AC018398 Genomic DNA. No translation available.
CH471153 Genomic DNA. Translation: EAW80474.1.
BC126200 mRNA. Translation: AAI26201.1.
BC126202 mRNA. Translation: AAI26203.1.
BC143902 mRNA. Translation: AAI43903.1.

IPI

IPI00005128.
IPI00181100.
IPI00793960.

RefSeq

NP_001112359.1. NM_001118887.1.
NP_001112360.1. NM_001118888.1.
NP_001138.1. NM_001147.2.

UniGene

Hs.583870.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1Z3S	X-ray	2.35	A/B	281-496	[»]
1Z3U	X-ray	2.25	A/B/C/D	281-496	[»]
2GY7	X-ray	3.70	A	281-495	[»]

ProteinModelPortal

O15123.

SMR

O15123. Positions 281-495.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-6048N.

IntAct

O15123. 3 interactions.

STRING

O15123.

PTM databases

PhosphoSite

O15123.

Proteomic databases

PRIDE

O15123.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000325203; ENSP00000314897; ENSG00000091879.

GeneID

285.

KEGG

hsa:285.

UCSC

uc003wqj.2. human.
uc010lri.1. human.

Organism-specific databases

CTD

285.

GeneCards

GC08M006347.

H-InvDB

HIX0034233.

HGNC

HGNC:485. ANGPT2.

HPA

CAB011437.
CAB017626.

MIM

601922. gene.

neXtProt

NX_O15123.

PharmGKB

PA24792.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG19777.

HOGENOM

HBG444111.

HOVERGEN

HBG001644.

InParanoid

O15123.

OMA

TWKEYKV.

OrthoDB

EOG4D7Z5N.

PhylomeDB

O15123.

Enzyme and pathway databases

Pathway_Interaction_DB

angiopoietinreceptor_pathway. Angiopoietin receptor Tie2-mediated signaling.

Reactome

REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

O15123.

Bgee

O15123.

CleanEx

HS_ANGPT2.

Genevestigator

O15123.

GermOnline

ENSG00000091879. Homo sapiens.

Family and domain databases

InterPro

IPR002181. Fibrinogen_a/b/g_C.
IPR014716. Fibrinogen_a/b/g_C_1.
IPR014715. Fibrinogen_a/b/g_C_2.
IPR020837. Fibrinogen_CS.
[Graphical view]

Gene3D

G3DSA:3.90.215.10. Fibrinogen_a/b/g_C_1. 1 hit.
G3DSA:4.10.530.10. Fibrinogen_a/b/g_C_2. 1 hit.

KO

K05466.

Pfam

PF00147. Fibrinogen_C. 1 hit.
[Graphical view]

SMART

SM00186. FBG. 1 hit.
[Graphical view]

SUPFAM

SSF56496. Fibrinogen_a/b/g_C. 1 hit.

PROSITE

PS00514. FIBRINOGEN_C_1. 1 hit.
PS51406. FIBRINOGEN_C_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

1151.

SOURCE

Search...

Entry information

Entry name

ANGP2_HUMAN

Accession

Primary (citable) accession number: O15123
Secondary accession number(s): A0AV38 , A8K205, B7ZLM7, Q9NRR7, Q9P2Y7

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	January 1, 1998
Last modified:	January 25, 2012
This is version 101 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.