New members of the chemokine receptor gene family - CiteSeerX

New members

of the chemokine

Carol J. Raport, Ronald Godiska, ICOS

Vicki L. Schweickart, David and Patrick W. Gray Bothell,

Corporation,

last

it ate,

Buffalo,

New

Abstract: Chemokines with potent chemoattractant for leukocytes. Several

receptor

Washington

York

98021;

and

Chantry,

gene family

Roger

L. Eddy,

of Human

*Depa,.tmepj

for human

are

relatively small peptides and activation activities chemokine receptors have

interleukin-8

reaction,

receptors

in response

have

Two first

time.

We

that

receptors

are

closely

close

have

seven to are

shown,

linked

with

association

gene

receptors. here for the

mapping

59:

Key Words: chromosome localization ceptor interleukin-8 - monocyte chemoattractant receptor

rela-

18-23; protein-coupled protein

G

.

kines

a family

are

vided into two groups: chemokines, contain and second cysteine have adjacent cysteine encoded

on

human

neutrophils. to human cytes,

to IL-8,

and

chromosome

lymphocytes,

coupled members proteins.

basophils, respond

transduce The

their

of

including

[9].

Amino

functionally

example,

C5a,

the

and

GPCRs The

related leukocyte

These

200

than

for

hormones,

identity

ligands

receptors

ranges

factor

cloning

18

Journal

techniques

of Leukocyte

were

the

from

Biology

monocyte

was

recently

have

For

was

RANTES

and

in response protein-i

by

Charo

causes

to both

ligands.

(MCP-1) and

receptor

colleagues

[17,

produces two splice variants that differ terminal domains. This receptor has reand

respond has

been

to MCP-3

in addi-

identified,

which

NAP-2,

GROa,

RANTES,

shares

-25%

identity

with

to span

may

not

signal

The

erythrocyte

been

shown

Abbreviations: IL-8,

interleukin-8;

chemokine seven

chemokine

20],

and

receptors. times,

Although this

receptor

mechanisms. has

expressed

subsequently

and

of chemokines

Epstein-Barr-induced human

MCP,

monocyte

protein;

MGSA,

neutrophil

[19,

may help

or aid

to

presenta-

to their targets [6]. Also known as the antigen, this molecule serves as a recep-

HUMSTSR,

yeast

receptor

widely

levels

EBI1,

receptor;

MCP-1

G protein-coupled

to be more

pled

YAC,

other

through

tion of chemokines Duffy blood group

reaction;

and

the membrane

circulating

recognized

1996

and

which IL-8,

NAP-2,

receptors

CCCKR1

re-

binds both CXC and CC chemokines. This receptor, was originally identified on red blood cells, binds

ity;

by

gene

carboxy

inflammatory

by molecu-

de-

[15] and by Gao and colboth monocyte inflamma-

chemoattractant

cently been shown to bind tion to MCP-i [18]. A promiscuous receptor

cyte

59, January

stimulatory

experiments

and

ion flux

characterized

f-Met-Leu-Phe,

neutrophil

Volume

The

and that

20-80%.

are each

two

GPCRs have chemoattracreceptors

that share 21-31% identity [10]. first chemokine receptors to be analyzed

lar

G

first

(MIP-la)

calcium

regulate

mole-

light,

among

chemoattractants

platelet-activating

are

heterotrimeric

receptors

peptide acid

G protein-

The

protein-la

it appears

mono-

transmembrane through

more

the

activate through

of seven signals

localized

eosinophils.

[4-8].

neurotransmitters,

odorants

bind

and

activate

are

generally

to chemokines

sequences

reported,

tants,

and

receptors (GPCRs) of a superfamily and

been

17

chemokines

growth

swapping

by Neote and colleagues [16]. This receptor binds

in their

J,

CC

receptors has led to a binding and signaling prop(IL-8RB) binds and signals

GRO/melanocyte

domain

strategies.

cloned leagues

18]. A single

a chemokines, also known as CXC a single amino acid between the first residues; the or CC, chemokines residues. The CXC chemokines are the

recombinant of their receptors

is termed

Chemobe subdi-

primarily

pri-

cloning

peptides

4 and

deduced

reorphan

related

chromosome

The

for CC chemokines have the use of homology-based

activation activity [1-3]. acids in length and can

In contrast,

Leukocytes

cules

of structurally

12].

Several receptors specific cently been identified with

INTRODUCTION are

[11,

(GRO/MGSA), and neutrophil activating peptide-2 while the other (IL-8RA) is specific for IL-8 [13].

intracellular

leukocyte 70-90 amino

(IL-8)

1996.

tory

Chemokines with potent

Cancer

termined critical residues for IL-8 binding [14] and have shown that binding specificity of the receptor is determined by the amino terminal extracellular domain [13].

similarity This

a functional

Biol.

activity (NAP-2), Mutagenesis

studies,

sequence chromosomes.

suggests

Leukoc.

as well.J.

novel

chemokine presented

the highest on human

with

genetic

tionship

identified

homology sequences

Park

B. Shows,*

mary sequences of these receptors share 76% identity and are clearly members of the GPCR superfamily. Cloning and expression of greater understanding erties. One of these

we

Roswell

Genetics,

members Using chain

significant of these

Thomas

14263

been cloned and characterized and all are ofthe G protein-coupled receptor superfamily. degenerate oligonucleotides and polymerase with

Jr.,t

activating artificial

1; GPCR,

7-transmembrane

C protein-cousegment

chemoattractant

protein;

receptor; MIP,

mono-

melanocyte

growth

stimulatory

activ-

peptide-2;

PCR,

polymerase

chain

chromosome.

Reprint requests: P.W. Gray, ICOS Corp., 22021 20th Ave. SE, Bothell, WA 98021. Received September 1, 1995; accepted September 26, 1995.

88-’2B CCCKR1 MCP1RA MCP1RB

MTTS. . . .LDTV MET? NTT MLSTSRSRFIRNT MLSTSRSRFIRNT

V28 EBI1

MDLGKPMKSVLVVALLVI MSNITDPQMWDF MESDSFEDFWKG MEGIS IYTSDNY MASG MEEG MNGL

IL8RA IL8RB RM3 R2 R20 R12

ETFGT. .TSYYD.D.VGLL.. EDYDT. .TTEFDYG.DATP.. NESGEEVTTFFDYD . YGAP.. NESGEEVTTFFDYD . YGAP.. H DQFPESVTENFEYDDLAEA. FQVCLCQDEVTDDY IGDNTTVDYTLFE DDLN. . . FTG.MPPADEDYSP EDLSNYSYSSTLPPFLLDAAP TEEMGSGDYDSMKEP NPWSSTLMRVSALTLQVLPTA. GDFDNYYGADNQ SE EVAPPGLITNFSLATAEQ...

F

IICFV

GQET

88-2B CCCKR1 MCP1RA MCP1RB V28 EBI1 IL8RA IL8RB RM3 R2 R20 R12

88-2B CCCKR1 MCP1RA MCP1RB V28 EBI1 IL8RA IL8RB RM3 R2 R20 R12

88-2B CCCKR1 MCP1RA MCP1RB V28 EBI1

IL8RA IL8RB RM3 R2 R20

R12

88-2B

Y

CCCKR1 MCP1RA MCP1RB V28 EBI1 IL8RA IL8RB RM3 R2 R20

.

.

.

.

T.

. .

.

. .

R12 Fig.

1

color:

cxc

.

found

chemokine

in sequence

are

receptors

(IL-8RA

introduced

to enhance

used

to design degenerate

previously

been

presented;

sequences

MCP-1RB [27],

and

(the R20

have

the been

two splice (same

of known chemokine receptors and related G protein-coupled receptors. Conserved residues are shown in receptors (CCCKR1, MCP-1RA, MCP-1RB, and 88-2b) are shown in yellow; residues found in both the and IL-8RB) are shown in pink; and residues common to all known chemokine receptors are shown in blue. Gaps

in all CC chemokine

sequences other

RYIPF.LPSEKLERTSSVS. . .PSTAEPELSIVF KWLPF.LSVDRLERVSSTS. . . . PSTGEHELSAGF . TTQGLLDGRGKGKSIGRAPEASLQDKEGA .FYRETVDGVTSTNT. . . PSTGEQEVSAGL . .VLCG RSVHVDFSSSESQRSRHGSVLSSNFTYHTSDGDALLL CLSQ EQLRQWSSCRHIRRSSMSV. . . . EAETTTTFSP LVSK EFLAR. . . .HRVTSYT.SS. . . .SVNVSSNL LISK DSLPK. . . .DSRPSFVGSS. . . .SGHTSTTL RGSSL KILSK. . .GKRGGHSSVST. . . .ESESSSFHSS GTG . SEASSTRRGGSLGQTARSGPAA . LEPGPSESLTASSPLKLNELN CAGTSHSSSGEKSASYSSGHSQGPGPNMGKGGEQMHEKS I PYSQETLVVD KRLKG. . PPPSFEGKTNES. . . .SLSAKSEL

of amino acid sequences

Alignment

residues

.MHLG .VHLV

DNA

published variants

as APi)

alignment

and

are

oligonucleotides sequences

represented

for PCR,

for these

genes

previously:

88-2b

(same

of the MCP-1

receptor

gene)

by dots.

which can

be found as

[17],

Putative

were used

transmembrane

to isolate

in Genbank

CCCKR3)

[32],

V28 [23],

orphan (accession

CCCKR1

EBI1

domains

receptors.

are

number

U33448

(MIP-1aIRANTES

[22, 26], IL-8RA

[11],

boxed.

Overlined

The sequences

for R2 and receptor)

IL-8RB

[12],

arrows

represent

for R2 and R 12 have [15, RM3

U33447 16], (same

for R12). MCP-1RA

not The and

as HUMSTSR)

[25].

Raport

et a!.

New

members

of the

chemokine

receptor

gene

family

19

pared with sequences

4 .

I

MCPIRA

25

26

23

29

31

31

35

39

MCP1RB

24

26

24

29

32

30

34

41

32

V28

Fig.

23

26

25

31

30

30

EBIl

24

25

26

31

34

31

ILIRA

26

28

25

34

76

ILSRB

26

29

25

34

RM3

24

27

23

R2

22

24

R20

30

2.

The

sented

protein

86

compared

with

ligands

have

[27],

and

and

is the R20

known not

same

is the

chemokine

yet

been

corresponding

as CCCKR3 same

as API

[32],

references

are

RM3

same

is the

preas

[25].

tor for the malarial parasite Plasmodium vivax. In addition to the mammalian chemokine receptors, two viral chemokine receptor homologues have been identified thus far. A gene product from Herpesvirus saimiri binds CXC chemokines and shares -‘30% identity with IL-8RA and IL-8RB [2i]. Human cytomegalovirus product, US28, that shares -30% identity

contains to the

CC

binds

MIP-1f3, biological chemokine

receptors;

of the

377

and

339

amino

this

receptor

a gene known MIP-lu,

of forming homologous

this

screen

also

chemokine tissues

[22,

and

26].

found

probe

known

significant

leukocytes

to the In

peripheral [23].

chemokine

receptors

and

lymphoid

B

to being

leukocytes,

R20,

or APJ,

(ref.

highly

ex-

V28

is

is 25-30%

and

27

lines

suggesting

addition

and kidney is 25-35%

tissues

with

cell

CCCKR1,

is

other

in lymphoid

blood

and

in

to

identity

receptors

lymph node, or HUMSTSR,

to re-

identified

32-35%

relationship.

chemokine

homologous angiotensin

It is expressed

tissues

capable

R2 is most angiotensin,

virus-transformed

and

placenta, RM3,

a

plots

regions

similarities

shares

identical

to known

brain [25], observations).

on

Hydropathy

seven

alpha helices. somatostatin,

for

EBI1

in neural

identical

is found

in

(unpublished identical

to

expressed

in

and

unpublished

observations).

CHROMOSOME

LOCALIZATION

5].

GPCR

genes

genome.

ISOLATION

OF ORPHAN to identify

RECEPTORS

additional

has utilized degenerate chain reaction (PCR)

chemokine

DNA template to these regions

receptors,

oligonucleotides to clone novel

our

and posequences

with degenerate primers correas previously described [22]. Six

unique sequences were identified R12, R20 (same as APi, ref. 25), induced 1 (EBI1) [22, 26], and 7-transmembrane segment receptor The derived amino acid sequences

by this approach: R2, V28 [23], Epstein-BarrRM3 [same as human (HUMSTSR), ref. 27]. of these genes are com-

20

Volume

of

Leukocyte

Biology

59,

are

distributed

Presented

throughout

in Figure

January

1996

and

function

opsin

are often

genes

are

chemotactic

peptide

mosome

19 [29].

closely [30].

related

Most

map some

hybrid

receptor

orphan

the are

of the

R2

[3i],

For are

and

shown R12 blots

as

example,

shown

several

receptors

in

Figure

and

1 do

The

were

Table

a 2 not

chromo-

determined

of mouse-human

in

four

on chro-

on chromosome

genes. genes

and

encoded

two IL-8

receptor

to Southern

DNA

for the entire superof similar structure

clustered

receptors

human of GPCR

X chromosome,

genes

chemokine

by hybridization

cell

the

In addition,

known

locations

linked.

on

pseudogene

of the

near

genes genes

closely

clustered

the

3 is a summary

gene localization [28]. Although family are broadly distributed,

[22, 23]. Comparison of the IL-8RA [1 i] and the angiotensin II receptor [24] revealed significant conservation between the following two distinct regions: the second transmembrane domain and the beginning of the second cytoplasmic domain. PCR was performed on a human

Journal

suggest

is 40%

also

genomic sponding

respectively.

Epstein-Barr

V28

Because of the broad diversity of chemokines and their activities, there are likely to be numerous receptors. The human sequences for at least eleven CXC and eight CC

In an effort

acids,

receptors.

functional

laboratory lymerase

not previously by cross-hy-

receptor

proteins

receptors.

in spleen

that are currently characterized therefore may represent only a fraction of the total complement of chemokine receptors. This proposal is strongly supported by binding and pharmacological studies on cell lines and human leuko-

orphan

exhibit

chemokine

pressed

chemokines have previously been determined [2, 3, 8] and several more have been identified by random cDNA sequencing efforts (unpublished observations). The receptors

i have isolated

and formyl peptides, whereas Ri2 is most the P2U purinoceptor, thrombin receptor, ceptor, and the orphan EBI1 [22]. The other four orphan receptor sequences

known

MCP-1, and RANTES [15]. Perhaps the potent effects of chemokines has led to the use of viral receptors for a selective pathological advan-

3,

their orphan

No introns were suggested by the which encode putative proteins of

membrane-spanning to the receptors

a close

[2,

Because

are termed

they

in Figure Ri2 were

APJ/R20

human genomic library. R2 and R12 sequences,

tage.

cytes

receptors.

defined,

sequences R2 and

of the two predicted

chemokine

in Figure 1. The GPCR superfamily,

receptors. Two of the been published.

sequences

1. 88-2b

receptors of the

and the majority are most similar to receptors for chemoattractant peptides. Sequence identity comparisons are presented in Figure 2 and range from 22 to 40% when

bridization

in Fig.

HUMSTSR

known chemokine are clearly members

somatic

1

.

Southern

blots of 31 hybrid DNAs were probed with the R2 sequence, and only the 19 lines containing the human chromosome fragment l4pter-14q23 yielded a band corresponding to the human R2 gene. The 12 hybrid lines

1

2

3

4

5

6

7

8

9

10

11

12

14

15

16

17

18

19

20

21

22

Y

0 13

0

Fig. 3.

Distribution

chromosomal on that

chromosome

cific

bands

brids

with

mosome

i4

an R12

probe

only

revealed

the

finely

genes

genes.

mapped.

to the

Likewise,

This

A dot data

murine

murine-spe-

screening

a band

in the 16 lines the 22 lines

only

not

receptor GPCR

on

human

below

was

chromosomes.

a chromosome

compiled

from

Dots

correspond

represents Ref.

28 and

a gene Online

to present

Mendelian

(http://gdbwww.gdb.org/omim/docs/omimtop.htmi).

hybridized

blots.

gene only 2pter-2q37; 2 showed

but

in Man

on Southern

the human chromosome

of individual

chromosome

Inheritance

lacking

of G protein-coupled

locations

38 hy-

corresponding

carrying lacking signal.

to

the human human chro-

Along

with

R2,

However, the V28 gene was not located on this YAC clone or on any overlapping clones. Subsequent studies determined that the V28 gene is at least 1,000 kbp distant from the known CCCKR1 same

chemokine and MCP-i

YAC

clone,

receptor receptors

and

genes. were

further

Nevertheless, found to be

mapping

studies

other GPCR genes that lie on chromosome i4 include those for the somatostatin, bradykinin, and thyroid-stimulating hormone receptors. R12 shares chromosome 2 with the genes that encode tachykinin, adrenergic, HUMSTSR, leuteinizing hormone/choriogonadotropin, and IL-8 recep-

taken. Using Southern blotting techniques, two receptors were shown to be within lished observations).

tors. The

the YAC DNA oligonucleotides,

other

viously

orphan

mapped:

q2i.2

[22],

receptors EBI1

is encoded

HUMSTSR

receptor

gene.

1 lq-i2 in the

V28

CCCKR1 receptor gene The close chromosomal quence

similarity

Yeast

artificial

ments

of genomic to identify

fied

by

quences.

i7q12-

2q23

[27],

at 3p2i-3pter

association

DNA,

near

and

500-1,000 YACs use

and

640

and encoded the genes for the MCP-1 receptor, as determined

specific

receptor and kbp of human

and were

to isolate quences, be

shown

identi-

receptor and and hybridization.

the

these

two regions

sixth

of the

sec-

transmembrane

presented

elsewhere

in Fig.

tity with the other orphans,

2, 88-2b known and

the

we found inophils.

the sequence The restricted

et a!.

New

members

of the

blots

fragments

clones. in Figure

GPCR sequences were then utilized One 1 and

(unpublished

chemokine also shows

Northern hybridization

to amplify

more novel fragments

shares

expression. significant

used

DNA was cloned and individIn addition to the CCCKR1

full-length cDNA 88-2b, is presented

such DNA

Raport

degenerate related se-

beginning

the

were

MCP-i receptors, two identified. The amplified

CC

V28. One genomic

i, the

PCR with identify

to

and

se-

We

for

in Figure domain

of YAC DNA. The amplified ual clones were sequenced.

length. was

for

that Using

domain are highly conserved among the CCCKR1 receptor, the MCP-i receptor, and V28. Degenerate oligonucleotides

seg-

and

a template we attempted

As shown

cytoplasmic

large V28

clones

primers

CCCKR1 by PCR

in

both

as

encoding

(as shown

contain

ond

underfor the (unpub-

proximity of these receptors suggested genes might be present on this YAC.

the

related. We the V28 gene.

kbp with

of YAC of

greater

receptors

(YAC)

A series the

CCCKR1 (MIP-1WRANTES) clone, 881F10, contained

pre-

V28 is the only one of of a known chemok-

chemokine

individual with

chromosome

V28 may be functionally to more precisely map

receptors. PCR

is found

chromosomes

hoped chemokine

that

[25]. vicinity

been

[23].

to known

in Fig. 2) suggest therefore attempted

on

1 have

is at chromosome

APi is at chromosome these genes that maps me

in Figure

The close novel related

were

genes 100 kbp

the the

on

much

of these the other

observations). greater

sequence

receptors than a very restricted

probed with to any human

88-2b tissues;

receptor

gene

As iden-

any of the pattern of showed no however,

to be abundantly expressed expression of 88-2b and

chemokine

sewill

family

in eosits high

21

TABLE

1.

Somatic

Cell

Hybrid

Chromosomal

Analysis

of R2

and

have

R12

Localization.

R2

R12

Number of Concordant Hybrids

Number of Discordant Hybrids

Number of Concordant Hybrids

Number of Discordant Hybrids

1

16

12

26

9

2

17

14

38

0

Chromosome

3

18

14

17

19

4

19

12

26

13

5

17

15

24

15

6

18

14

25

14

7

19

12

21

17

8

17

15

21

18

24

12

engineered

their

examined

signal

signaling

through

signal

the

transduction

cellular mine

whether

known

We

have

our

orphan

chemokines.

cloned behind and were used Individual of receptor were

in mammalian effects.

respond

sequences

the cytomegalovirus to make stable

loaded

with

cellular

calcium responses

the

Ca2+sensing

ion

flux

9

15

10

18

14

19

19

Positive

11

16

12

24

12

12

19

13

22

17

8RA when stimulated receptor was stimulated

13

19

13

21

18

14

31

0

24

14 15

no calcium

was

first

of pRc/CMV in 293 cells.

Fura

measured

observed

2, and

intra-

fluorometrically.

in

cells

with IL-8 and with MCP-i observed

of the

were

chosen for high levels transfected 293 cells dye

was

were

flux

were The

to deter-

to any

promoter transfectants

transfectant clones RNA production.

of inn-a-

assay

receptor

of

is that

release

this

receptors

The

14

the

used

and

feature

receptors

with

therefore

cells

A common

chemokine

is associated

Ca2+.

known

expression

transduction

expressing

also when or MCP-3.

in cells

IL-

the MCP-i However,

expressing

EBI1

or

88-2b after addition of various chemokines. A very weak, but reproducible, response was seen in cells expressing V28 when stimulated with MCP-3. This lack of signal

15

14

17

23

16

18

14

20

19

17

21

10

23

14

18

21

11

21

18

19

13

19

28

11

20

16

16

22

17

21

18

14

21

18

binant receptors may not be functionally expressed cell surface; (2) the orphan receptor may not cause

22

13

18

22

15

transduction

x

12

16

14

18

the

transduction

R2 and R12 probes were hybridized to Southern blots of DNA from humanmouse cell hybrids. The hybrids were characterized for human chromosome content by karyotypic analysis and by mapped enzyme markers. Segregation of 112 and R12 hybridization with the presence of each human chromosome is summarized. A lack of discordancy indicates the matched segregation of the probed human band with a chromosome. By this analysis R2 was localized to chromosome 14 and R12 to chromosome 2. A hybrid with the translocation 1 lqter-1 1p13::14q23-l4qter and no intact chromosome 14 scored negative for R2, localizing 82 to the l4pter-14q23 region. A hybrid with the translocation 2pter-2q37::1p21-lpter and no intact chromosome 2 scored positive for R12, localizing R12 to 2pter-2q37.

may

via

not appear

tested.

to be

at least

uncharacterized; specific

here.

Future

flux;

(3)

characterization

such will

of these

the

novel

many

receptors

(1)

293

the

cells

to

as

the aimed

receptors

and

novel

may

latter,

there

currently chemokines

orphans at

lack

down-

ligand

the novel

be

on the signal

may

chemokines

of these

recom-

or other proper

respect

10-20

experiments

the

(4)

With

perhaps

factors:

of G proteins

components;

been

bind

to several

complement

signaling

have

due

calcium

appropriate

stream

be

presented the

functional

chemokines.

ACKNOWLEDGMENTS sequence

similarity

and

close

chromosomal

the CC chemokine be a CC chemokine

receptors receptor

taxis. Studies isolated the

from sequence

other laboratories have demonstrated

does indeed colleagues,

encode a CC chemokine who have named the

proximity

that

to

would chemo-

The

independently that this cDNA

and

suggested that 88-2b involved in eosinophil

receptor. Murphy clone CCCKR3,

and have

demonstrated that the receptor binds RANTES and MIPlcx and triggers Ca2+ flux in response to these chemokines [32]. Gerard et al. have reported that this receptor functions in response me Symposium). chemokine phils

to eotaxin Eotaxin

whose

effects

(Fourth International Chemokis a recently described CC appear

to be restricted

to eosino-

[33].

Wood

ANALYSIS

1.

2.

3.

5.

OF CHEMOKINE

6.

Chemokines have causing chemotaxis,

potent cellular activities on leukocytes, shape change, increased adhesivity,

and release of granule enzymes tors. To examine the functional

22

Journal

of

Leukocyte

Biology

and other bioactive mediarole of orphan receptors, we

Volume

59,

January

1996

for Larry

gratefully DNA Tjoelker

thank

sequencing for

critical

Dma and

Leviten

oligonucleotide review

of the

and

Christi synthesis

manuscript.

REFERENCES

4.

FUNCTIONAL RECEPTORS

authors

7. 8. 9.

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Sequencealignmentofthc Gprotein-coupled receptorsuperfamily. DNA Cell 1 1, 1-20. Murphy, P.M. (1994) The molecular biology of lcukocytc chemoattractant receptors. Anna. Rev. Immwzol. 12, 593-633. Holmes,W.E.,Lec,J., Kuang,W-J.,Rice,G.C.,Wood,W.I.(1991)Structure and functional expression of a human intcrleukin-8 receptor. Science 253, 1278-1280. Murphy, P.M., Tiffany, H.L (1991) Cloning ofcomplcmentary DNA encoding a functional human interleukin-8 receptor. Science 253, 1280-1283. Lee, j., Honik, R., Rice, G.C., Bennett, G.L, Camerato, 1., Wood, WI. (1992) Characterization oftwo high affinity human interlcukin-8 receptors. J. Bid. Chem. 267, 16283-16287. Leong, S.R., Kabakoff, R.C., Hebcrt, C.A. (1994) Complete mutagenesis of the extraccllular domain of intcrleukin-8 (IL-8) type A receptor identifies charged residues mediating IL.8 binding and signal transduction. J. Biol. Chem. 269, 19343-19348. Neote, K., DiGregorio, D., Mak, J.Y., Horuk, R., Schall, TJ. (1993) MolecuJar cloning, functional expression. and signalling characteristics of a C-C chemokine receptor. Cell 72, 415-425. Gao, J.-L, Kuhns, D.B., Tiffany, H.L, McDermott, D., Li, X., Francke, U., Murphy, P.M. (1993) Structure and functional expression of the human macrophage inflammatory protein la/RANTES receptor.). Exp. Med. 177, 1421-1427. Charo, I.F., Myers, SJ.. Herman, A., Franci, C., Connolly, AJ., Coughlin, S.R. (1994) Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals atternative splicing of the carboxyl-tenninal tails. Proc. Nail. Acad. Sci. USA 91, 2752-2756. Myers, SJ., Wong, L.M., Charo, I.F. (1995) Signal transduction and ligand specificity of the human monocyte chemoattractant protein-i receptor in transfected embryonic kidney cells. J. Bid. Chem. 270, 5786-5792. Horuk, R., Chitnis, C.E., Darbonne, W.C., Colby, TJ., Rybicki, A., Hadley, TJ., Miller, LH. (1993) A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor. Science 261, 1182-1184. Neote, K., Darbonne, W., Ogez,J., Horuk, R., Schall,TJ. (1993) Identification of a promiscuous inflammatory peptide receptor on the surface of red blood cells. J. Biol. Chem 268, 12245-12249. Ahuja, S.K., Murphy, P.M. (1993) Molecular piracy of mammalian interleukin-8 receptor type B by Herpesvirus saimin. J. Biol. Chem. 268, 20691-20694. Schweickart, V.L, Raport, CJ., Godiska, R., Byers, M.G., Eddy, R.L, Jr., Shows, T.B., Gray, P.W. (1994) Cloning of human and mouse EBI1, a lymphoid-specific G protein-coupled receptor encoded on human chromoBiOS.

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some 17q12-q2l.2. Genomics 23, 643-650. Raport, CJ., Schweickart, V.L, Eddy, R.L, Jr., Shows, TB., Gray, P.W. (1995) The orphan C protein-coupled receptor-encoding gene V28 is closely related to genes for chemokinc receptors and is expressed in lymphoid and neural tissues. Gene 163,295-299. Sasaki, K., Yamano, Y., Bardhan, S., lwai, N., Murray, Jj., Hasegawa, M., Matsuda, Y., lnagami, T. (1991) Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type- 1 receptor. Nature 351, 230-232. O’Dowd, B.F., Heiber, M., Chan, A., Heng, H.H.Q., Tsui, L-C., Kennedy, iL, Shi, X., Petronis, A., George, S.R., Nguyen, T. (1993) A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 1 1. Gene 136,355-360. Birkenbach, M., Josefsen, K., Yalamanchili, R., Lenoir, G., and Kieff, E. (1993) Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors. J. Virol. 67, 2209-2220. Federsppicl, B., Melhado, I.G., Duncan, A.M.V.. Delaney, A., Schappert, K., Clark-Lewis, I., Jirik, FR. (1993) Molecular cloning of the eDNA and chromosomal localization of the gene for a putative scven-transmembrane segment (7-TMS) receptor isolated from human spleen. Genomics 16, 707-712. McAlpine, Pj., Shows, TB., Povey, S., Carritt, B., Pericak-Vance, MA., Boucheix, C., Anderson, WA., White, J.A. (1994) The 1993 catalog of approved genes and report of the nomenclature committee. In Human Gene Mapping, 1993. (AJ. Caticchia and P.L. Pearson, eds), The Johns Hopkins University Press, Baltimore, MD, 6-124. Gerard, NP., Bao, L, Xiao-Ping, H., Eddy, R.L., Jr., Shows, TB., Gerard, C. (1993) Human chemotaxis receptor genes cluster at 19qi3.3-i3.4: characterization ofthe human C5a receptor gene. Biochemistry 32, 1243-1250. Ahuja, S.K., Ozcelik, T., Milatovitch, A., Francke, U., Murphy, P.M. (1992) Molecular evolution ofthe human interleukin-8 receptorgene cluster. Nature Can. 2, 31-36. Shows, TB., Sakaguchi, A.Y., Naylor, S.L. (1982) Mapping the human genome, cloned genes, DNA polyorphisms, and inherited disease. Adv. Human Genet. 12, 341-452. Combadiere, C., Ahuja, S.K., Murphy, P.M. (1995) Cloning and functional expression of a human eosinophil CC chemokine receptor. J. Biol. Chem. 270, 16491-16494. Jose, PJ., Griffiths-johnson, D.A., Collins, PD., Walsh, D.T., Moqbel, R., Totty. N.F., Truong, 0., Hsuan, Jj., Williams, TJ. (1994) Eotaxin: a potent cosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation.). Exp. Med. 179, 881-887.

New

members

of

the

chemokine

receptor

gene

family

23