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Hepatocyte growth factor receptor

Summary

UniProt ID: P08581
Gene Symbol: MET
Gene ID: 4233
Organism: Homo sapiens (human)

External Links

GlycoProtDB

GPDB0011442

GlyConnect

Hepatocyte growth factor receptor

GlyGen

P08581

PubChem

P08581

The Human Metabolome Database

HMDBP09447

The O-GlcNAc Database

P08581

RaftProt

P08581

O-GlcNAcAtlas

P08581

Re-Glyco

P08581

Annotation

Keyword: 3D-structure ATP-binding Alternative splicing Chromosomal rearrangement Disease variant Disulfide bond Glycoprotein Non-syndromic deafness Phosphoprotein Proteomics identification Proto-oncogene Receptor Reference proteome Repeat Secreted Signal Transmembrane helix Tyrosine-protein kinase Ubl conjugation

Gene Ontology (GO)

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GO Term	Evidence Code	Reference
endothelial cell morphogenesis	IDA	PMID
liver development	IBA	GO_REF
cell surface receptor signaling pathway	NAS	PMID
cell surface receptor protein tyrosine kinase signaling pathway	IBA	GO_REF
cell surface receptor protein tyrosine kinase signaling pathway	IEA	GO_REF

GO Hierarchy

biological process

cellular process [inference]

signal transduction [inference]

cell surface receptor signaling pathway

enzyme-linked receptor protein signaling pathway [inference]

cell surface receptor protein tyrosine kinase signaling pathway

hepatocyte growth factor receptor signaling pathway

semaphorin-plexin signaling pathway

cellular developmental process [inference]

cell differentiation [inference]

neuron differentiation

multicellular organismal process [inference]

morphogenesis of a branching structure [inference]

morphogenesis of a branching epithelium [inference]

branching morphogenesis of an epithelial tube

developmental process [inference]

anatomical structure morphogenesis [inference]

cell morphogenesis [inference]

epithelial cell morphogenesis [inference]

endothelial cell morphogenesis

morphogenesis of a branching structure [inference]

morphogenesis of a branching epithelium [inference]

branching morphogenesis of an epithelial tube

tube morphogenesis [inference]

branching morphogenesis of an epithelial tube

tissue morphogenesis [inference]

morphogenesis of an epithelium [inference]

morphogenesis of a branching epithelium [inference]

branching morphogenesis of an epithelial tube

anatomical structure development [inference]

animal gross anatomical part developmental process [inference]

animal organ development [inference]

pancreas development

gland development [inference]

liver development

cellular developmental process [inference]

cell differentiation [inference]

neuron differentiation

locomotion [inference]

taxis [inference]

chemotaxis [inference]

positive chemotaxis

biological regulation [inference]

regulation of biological process [inference]

regulation of locomotion [inference]

positive regulation of locomotion [inference]

positive regulation of chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

positive regulation of cell motility [inference]

positive regulation of cell migration [inference]

positive regulation of endothelial cell migration [inference]

positive regulation of endothelial cell chemotaxis

regulation of chemotaxis [inference]

positive regulation of chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

regulation of endothelial cell chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

regulation of cell motility [inference]

regulation of cell migration [inference]

regulation of endothelial cell migration [inference]

positive regulation of endothelial cell migration [inference]

positive regulation of endothelial cell chemotaxis

regulation of endothelial cell chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

positive regulation of cell migration [inference]

positive regulation of endothelial cell migration [inference]

positive regulation of endothelial cell chemotaxis

positive regulation of cell motility [inference]

positive regulation of cell migration [inference]

positive regulation of endothelial cell migration [inference]

positive regulation of endothelial cell chemotaxis

positive regulation of biological process [inference]

positive regulation of locomotion [inference]

positive regulation of chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

positive regulation of cell motility [inference]

positive regulation of cell migration [inference]

positive regulation of endothelial cell migration [inference]

positive regulation of endothelial cell chemotaxis

positive regulation of cellular process [inference]

positive regulation of metabolic process [inference]

positive regulation of biosynthetic process [inference]

positive regulation of macromolecule biosynthetic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of macromolecule metabolic process [inference]

positive regulation of macromolecule biosynthetic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of RNA metabolic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of cell motility [inference]

positive regulation of cell migration [inference]

positive regulation of endothelial cell migration [inference]

positive regulation of endothelial cell chemotaxis

positive regulation of response to stimulus [inference]

positive regulation of response to external stimulus [inference]

positive regulation of chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

negative regulation of biological process [inference]

negative regulation of cellular process [inference]

negative regulation of metabolic process [inference]

negative regulation of catabolic process [inference]

negative regulation of autophagy

negative regulation of programmed cell death [inference]

negative regulation of hydrogen peroxide-mediated programmed cell death

regulation of response to stimulus [inference]

regulation of response to external stimulus [inference]

positive regulation of response to external stimulus [inference]

positive regulation of chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

regulation of chemotaxis [inference]

positive regulation of chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

regulation of endothelial cell chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

positive regulation of response to stimulus [inference]

positive regulation of response to external stimulus [inference]

positive regulation of chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

regulation of cellular process [inference]

signal transduction [inference]

cell surface receptor signaling pathway

enzyme-linked receptor protein signaling pathway [inference]

cell surface receptor protein tyrosine kinase signaling pathway

hepatocyte growth factor receptor signaling pathway

semaphorin-plexin signaling pathway

regulation of metabolic process [inference]

regulation of biosynthetic process [inference]

positive regulation of biosynthetic process [inference]

positive regulation of macromolecule biosynthetic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

regulation of macromolecule biosynthetic process [inference]

regulation of gene expression [inference]

regulation of DNA-templated transcription [inference]

regulation of transcription by RNA polymerase II [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of macromolecule biosynthetic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

regulation of RNA biosynthetic process [inference]

regulation of DNA-templated transcription [inference]

regulation of transcription by RNA polymerase II [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

negative regulation of metabolic process [inference]

negative regulation of catabolic process [inference]

negative regulation of autophagy

positive regulation of metabolic process [inference]

positive regulation of biosynthetic process [inference]

positive regulation of macromolecule biosynthetic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of macromolecule metabolic process [inference]

positive regulation of macromolecule biosynthetic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of RNA metabolic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

regulation of catabolic process [inference]

negative regulation of catabolic process [inference]

negative regulation of autophagy

regulation of autophagy [inference]

negative regulation of autophagy

regulation of macromolecule metabolic process [inference]

regulation of macromolecule biosynthetic process [inference]

regulation of gene expression [inference]

regulation of DNA-templated transcription [inference]

regulation of transcription by RNA polymerase II [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of macromolecule biosynthetic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

regulation of RNA biosynthetic process [inference]

regulation of DNA-templated transcription [inference]

regulation of transcription by RNA polymerase II [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of macromolecule metabolic process [inference]

positive regulation of macromolecule biosynthetic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of RNA metabolic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

regulation of RNA metabolic process [inference]

positive regulation of RNA metabolic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

regulation of RNA biosynthetic process [inference]

regulation of DNA-templated transcription [inference]

regulation of transcription by RNA polymerase II [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

regulation of primary metabolic process [inference]

regulation of nucleobase-containing compound metabolic process [inference]

regulation of RNA metabolic process [inference]

positive regulation of RNA metabolic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

regulation of RNA biosynthetic process [inference]

regulation of DNA-templated transcription [inference]

regulation of transcription by RNA polymerase II [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

regulation of programmed cell death [inference]

negative regulation of programmed cell death [inference]

negative regulation of hydrogen peroxide-mediated programmed cell death

regulation of hydrogen peroxide-mediated programmed cell death [inference]

negative regulation of hydrogen peroxide-mediated programmed cell death

positive regulation of cellular process [inference]

positive regulation of metabolic process [inference]

positive regulation of biosynthetic process [inference]

positive regulation of macromolecule biosynthetic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of macromolecule metabolic process [inference]

positive regulation of macromolecule biosynthetic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of RNA metabolic process [inference]

positive regulation of RNA biosynthetic process [inference]

positive regulation of DNA-templated transcription [inference]

positive regulation of transcription by RNA polymerase II

positive regulation of cell motility [inference]

positive regulation of cell migration [inference]

positive regulation of endothelial cell migration [inference]

positive regulation of endothelial cell chemotaxis

negative regulation of cellular process [inference]

negative regulation of metabolic process [inference]

negative regulation of catabolic process [inference]

negative regulation of autophagy

negative regulation of programmed cell death [inference]

negative regulation of hydrogen peroxide-mediated programmed cell death

regulation of cell motility [inference]

regulation of cell migration [inference]

regulation of endothelial cell migration [inference]

positive regulation of endothelial cell migration [inference]

positive regulation of endothelial cell chemotaxis

regulation of endothelial cell chemotaxis [inference]

positive regulation of endothelial cell chemotaxis

positive regulation of cell migration [inference]

positive regulation of endothelial cell migration [inference]

positive regulation of endothelial cell chemotaxis

positive regulation of cell motility [inference]

positive regulation of cell migration [inference]

positive regulation of endothelial cell migration [inference]

positive regulation of endothelial cell chemotaxis

regulation of biological quality [inference]

regulation of membrane potential [inference]

regulation of postsynaptic membrane potential [inference]

excitatory postsynaptic potential

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GO Term	Evidence Code	Reference
extracellular region	IEA	GO_REF
plasma membrane	TAS	PMID Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome Reactome
plasma membrane	IBA	GO_REF
basal plasma membrane	IDA	PMID
basal plasma membrane	IBA	GO_REF

GO Hierarchy

cellular component

protein-containing complex [inference]

signaling receptor complex

cellular anatomical structure [inference]

membrane

plasma membrane

plasma membrane region [inference]

basal plasma membrane

postsynapse

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GO Term	Evidence Code	Reference
protein tyrosine kinase activity	NAS	PMID
protein tyrosine kinase activity	TAS	Reactome
protein tyrosine kinase activity	IEA	GO_REF GO_REF GO_REF
hepatocyte growth factor receptor activity	TAS	PMID
hepatocyte growth factor receptor activity	IBA	GO_REF

GO Hierarchy

molecular function

catalytic activity [inference]

transferase activity [inference]

transferase activity, transferring phosphorus-containing groups [inference]

kinase activity [inference]

protein kinase activity [inference]

protein tyrosine kinase activity

transmembrane receptor protein tyrosine kinase activity [inference]

hepatocyte growth factor receptor activity

transmembrane receptor protein kinase activity [inference]

transmembrane receptor protein tyrosine kinase activity [inference]

hepatocyte growth factor receptor activity

phosphotransferase activity, alcohol group as acceptor [inference]

protein kinase activity [inference]

protein tyrosine kinase activity

transmembrane receptor protein tyrosine kinase activity [inference]

hepatocyte growth factor receptor activity

transmembrane receptor protein kinase activity [inference]

transmembrane receptor protein tyrosine kinase activity [inference]

hepatocyte growth factor receptor activity

catalytic activity, acting on a protein [inference]

protein kinase activity [inference]

protein tyrosine kinase activity

transmembrane receptor protein tyrosine kinase activity [inference]

hepatocyte growth factor receptor activity

transmembrane receptor protein kinase activity [inference]

transmembrane receptor protein tyrosine kinase activity [inference]

hepatocyte growth factor receptor activity

binding [inference]

protein binding [inference]

enzyme binding [inference]

phosphatase binding [inference]

protein phosphatase binding

identical protein binding

small molecule binding [inference]

ion binding [inference]

anion binding [inference]

purine ribonucleoside triphosphate binding [inference]

ATP binding

heterocyclic compound binding [inference]

nucleotide binding [inference]

purine nucleotide binding [inference]

adenyl nucleotide binding [inference]

adenyl ribonucleotide binding [inference]

ATP binding

purine ribonucleotide binding [inference]

adenyl ribonucleotide binding [inference]

ATP binding

ribonucleotide binding [inference]

purine ribonucleotide binding [inference]

adenyl ribonucleotide binding [inference]

ATP binding

purine ribonucleoside triphosphate binding [inference]

ATP binding

carbohydrate derivative binding [inference]

ribonucleotide binding [inference]

purine ribonucleotide binding [inference]

adenyl ribonucleotide binding [inference]

ATP binding

nucleoside phosphate binding [inference]

nucleotide binding [inference]

purine nucleotide binding [inference]

adenyl nucleotide binding [inference]

adenyl ribonucleotide binding [inference]

ATP binding

purine ribonucleotide binding [inference]

adenyl ribonucleotide binding [inference]

ATP binding

ribonucleotide binding [inference]

purine ribonucleotide binding [inference]

adenyl ribonucleotide binding [inference]

ATP binding

purine ribonucleoside triphosphate binding [inference]

ATP binding

molecular transducer activity [inference]

signaling receptor activity [inference]

transmembrane signaling receptor activity [inference]

semaphorin receptor activity

transmembrane receptor protein kinase activity [inference]

transmembrane receptor protein tyrosine kinase activity [inference]

hepatocyte growth factor receptor activity

molecular function regulator activity [inference]

molecular function activator activity

Gene Ontology information from UniProt.

Annotation information from UniProt.

Sequence

MKAPAVLAPGILVLLFTLVQRSNGECKEALAKSEMNVNMKYQLPNFTAETPIQNVILHEHHIFLGATNYIYVLNEEDLQKVAEYKTGPVLEHPDCFPCQDCSSKANLSGGVWKDNINMALVVDTYYDDQLISCGSVNRGTCQRHVFPHNHTADIQSEVHCIFSPQIEEPSQCPDCVVSALGAKVLSSVKDRFINFFVGNTINSSYFPDHPLHSISVRRLKETKDGFMFLTDQSYIDVLPEFRDSYPIKYVHAFESNNFIYFLTVQRETLDAQTFHTRIIRFCSINSGLHSYMEMPLECILTEKRKKRSTKKEVFNILQAAYVSKPGAQLARQIGASLNDDILFGVFAQSKPDSAEPMDRSAMCAFPIKYVNDFFNKIVNKNNVRCLQHFYGPNHEHCFNRTLLRNSSGCEARRDEYRTEFTTALQRVDLFMGQFSEVLLTSISTFIKGDLTIANLGTSEGRFMQVVVSRSGPSTPHVNFLLDSHPVSPEVIVEHTLNQNGYTLVITGKKITKIPLNGLGCRHFQSCSQCLSAPPFVQCGWCHDKCVRSEECLSGTWTQQICLPAIYKVFPNSAPLEGGTRLTICGWDFGFRRNNKFDLKKTRVLLGNESCTLTLSESTMNTLKCTVGPAMNKHFNMSIIISNGHGTTQYSTFSYVDPVITSISPKYGPMAGGTLLTLTGNYLNSGNSRHISIGGKTCTLKSVSNSILECYTPAQTISTEFAVKLKIDLANRETSIFSYREDPIVYEIHPTKSFISGGSTITGVGKNLNSVSVPRMVINVHEAGRNFTVACQHRSNSEIICCTTPSLQQLNLQLPLKTKAFFMLDGILSKYFDLIYVHNPVFKPFEKPVMISMGNENVLEIKGNDIDPEAVKGEVLKVGNKSCENIHLHSEAVLCTVPNDLLKLNSELNIEWKQAISSTVLGKVIVQPDQNFTGLIAGVVSISTALLLLLGFFLWLKKRKQIKDLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFPEDQFPNSSQNGSCRQVQYPLTDMSPILTSGDSDISSPLLQNTVHIDLSALNPELVQAVQHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLDNDGKKIHCAVKSLNRITDIGEVSQFLTEGIIMKDFSHPNVLSLLGICLRSEGSPLVVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKFVHRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAKLPVKWMALESLQTQKFTTKSDVWSFGVLLWELMTRGAPPYPDVNTFDITVYLLQGRRLLQPEYCPDPLYEVMLKCWHPKAEMRPSFSELVSRISAIFSTFIGEHYVHVNATYVNVKCVAPYPSLLSSEDNADDEVDTRPASFWETS

N : N-glycosylation Site
___ : Potential Sequon

Glycosylation Sites

Displaying entries **1 - 10** of 21 in total

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Position	Description	PubMed ID	GlyTouCan ID	Source
45	N-linked (GlcNAc...) asparagine			UniProt GlyGen
106	N-linked (GlcNAc...) asparagine	19196183 23090970 24190977 29391424 37074911	G50856PC G56518TU G93656SY G80479JV G07246CJ G43223CG G06356OH G80920RR G62765YT	GlycoProtDB UniProt GlyGen GlyConnect
149	N-linked (GlcNAc...) asparagine	24190977	G80920RR	UniProt GlyGen
199		24190977		GlyGen
202	N-linked (GlcNAc...) asparagine		G65184UU	UniProt GlyGen
393		24190977		GlyGen
399	N-linked (GlcNAc...) asparagine	23090970 24190977 37074911	G81637OR G50856PC G39471UU G55132BD G35541EV G93718GY G13131HA G80075MS G16125XL G29545VG G68490OW G60834IK G86880BF G90382BL G80479JV G85282JO G87123QX G79666IR G34989PA G45395BF G07246CJ G10819WX G14972EH G43223CG G58954YZ G37412TK G08918WF G61256FT G70441OD G87661QW G83646BJ G76295SF G27058EU G83460ZZ G41071NU G92406TI G80920RR G62765YT	GlycoProtDB UniProt GlyGen
405	N-linked (GlcNAc...) asparagine	23345538 37074911	G07246CJ G43223CG G41071NU G31916IQ G45504EY	GlycoProtDB UniProt GlyGen GlyConnect
582	O-linked (Man) threonine	37186866		UniProt GlyGen
607	N-linked (GlcNAc...) asparagine	23090970 24190977 37074911	G82443XX G90382BL G62765YT G37995HC	GlycoProtDB UniProt GlyGen

Feature

: Glycosylation Site from GlyGen
: Glycosylation Site from UniProt

Pathway

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Pathway Name	Organism
Constitutive Signaling by Aberrant PI3K in Cancer	Homo sapiens
Drug-mediated inhibition of MET activation	Homo sapiens
InlB-mediated entry of Listeria monocytogenes into host cell	Homo sapiens
MECP2 regulates neuronal receptors and channels	Homo sapiens
MET Receptor Activation	Homo sapiens
MET activates PI3K/AKT signaling	Homo sapiens
MET activates PTK2 signaling	Homo sapiens
MET activates PTPN11	Homo sapiens
MET activates RAP1 and RAC1	Homo sapiens
MET activates RAS signaling	Homo sapiens

Human Protein Atlas

ENSG00000105976

Tissue with high expression from Human Protein Atlas. Tissues that are highly expressed are highlighted.

Data available from v23.0.proteinatlas.org. Image credit: Human Protein Atlas

Disease

Displaying **all 8** entries
DO ID	Disease Name	Source
DOID:4465	papillary renal cell carcinoma	Alliance of Genome Resources
DOID:4552	large cell carcinoma	Alliance of Genome Resources
DOID:4450	renal cell carcinoma	Alliance of Genome Resources
DOID:0050646	distal arthrogryposis	Alliance of Genome Resources
DOID:9538	multiple myeloma	Alliance of Genome Resources
DOID:0110539	autosomal recessive nonsyndromic deafness 97	Alliance of Genome Resources
DOID:684	hepatocellular carcinoma	Alliance of Genome Resources
DOID:12849	autistic disorder	Alliance of Genome Resources

GlyTouCan

GlyComb

GlycoPOST

UniCarb-DR

LM-GlycoRepo

All Resources

Other Information

Tools

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Summary

External Links

Annotation

International Collaboration

Acknowledgements