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1990.6: 597-641

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Annu. Rev. Cell. Biol. 1990.6:597-641. Downloaded from www.annualreviews.org by University of British Columbia on 02/16/13. For personal use only.

THE TRANSFORMING GROWTH FACTOR-/J FAMILY Joan Massague H oward Hug hesM ed ci al In st itut e and C ell Bi ology and G en et ci s Pr ogram , New York 1 0 0 2 1 KEY WORDS:

growth inhibitors/suppressors, cell differentiation, cell adhesion, growth factor receptors, transformations

CONTENTS INTRODUCTION..............................................................................................................

598

{3 SUPERFA MILy................................................................................................ Prototype Structure ................................................................ .................................. TGFs-{3: Forms, Expression, and Regulation ............................................................ lnhibins and Activins................................................................................................. Decapentaplegic, Vgl, and BMPs............................................................................. Mullerian Inhibiting Substance .................................................................... .. .........

598 601 605 606 607

THE TGF-

.

.

. ............................................... ............ P Control oj Cell Proliferation..................................................................................... Control oJ Cell Adhesion ............................................................................. ............ Control oJ Cell Phenotype ........................................................................... ............ Physiology and Pathology ........................................................................................

BIOLOGICAL ACTIONS OF TGF-

...... ...................

.

.

.

{3 RECEPTORS AND OTHER BINDING PROTEINS........................................................... TGF-{3 Receptors ......................................................................................... ............ Bet�g.'yca.ns:. Proteoglrcans with High Affinity Jor TGF-{3........................................ ActlVm Bmdmg Protems ...........................................................................................

TGF-

.

598

608 609 610 613 616 618 619 622 623

{3 ACTION ....................................................................................... The Cytoplasmic Response ....... ........ ... ....... .. ............................ ....................... The Nuclear Response .............................................................................................. Growth Suppression Mechanisms.............................................................................. Differentiation Control Mechanisms ......................................................... .. ............

624 625 626

.. . ...... ............... . .................................................... ..........................

629

MECHANISMS OF TGF-

.

.

.

..

.

...

.

PROSPECTS ...... .. ..

.

.

.

624

628

597 07 43-463 4 9/ 0 1/ 1 1 5 -0

598

MASSAGuE

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INTRODUCTION Secretory polypeptidesa re broa dly useda s media tors of intercellula r com· munica tion to guide tissue development in metaz oa . A deca de a go, a s the cha ra cteriza tion of va rious mitogenic polypeptides a nd the isola tion oj scores of new ones were in progress, sea rches were la unched to identif) novel fa ctors with a ctivities other tha n promotion of cell growth. Some oj the fruitful sea rches led to the is ola tion of a promoter ofa tra nsformed phenotype in fibrobla sts, a n inhibitor of cell prolifera tion, a n inducer oj chondrogenic differentia tion,a n inhibitor of myogenic differentia tion,a nd a n immunosuppressor. It wa s a ma jor surprise to find tha t a single fa ctoI wa s responsible for a ll of these a ctivities. Tra nsforming gr owth fa ctor type-[3 , or TGF-[3 , beca me the conventiona l na me for this multifunctional fa ctor, even though this na me misrepresents the fa ct tha t TGF-[3 does not ca use oncogenic tra nsforma tion. Besides being multifunctiona l, TGF-[3 represents a la rge fa mily of fa c­ tors with diverse a ctivities. The concept tha t TGF-[3 is prototypic of a superfa mily of growth, differentia tion,a nd morphogenesis fa ctors beca me cl ear in 1987 (Massague 1987; Sporn et a11987) following the rich harvest tha t yielded the inhibins, a ctivins, Mulleria n inhibiting subs ta nce, deca ­ penta plegic product,a nd TGF-f3 2. Onea ftera nother, these fa ctors proved to be structura lly rela ted to TGF-f3 . This fa mily now includes embryogenic morphogens, regula tors of endocrine function, a nd broa d-spectrum a s w ell a s sp ecia lized reg ula tors ofc el lp rolifera tion a nd differentia tion. The distribution of TGF-f3 -rela ted fa ctors is widesprea d in orga nisms f rom frui t fl ies to huma ns, a nd their evolutiona ry conserva tion is unusua lly strict. These fa ctors a ppea r to be involved in ma ny processes of tissue development a nd repa ir. W e ha ve lea rned much a bout the structure, expression, a nd a ctivity of the TGF-f3 -rela ted fa ctors, a nd their implica tions in physiology, pa thol­ ogy, a nd thera peutics. Some glimpses of their receptors a nd mecha nisms of a ction ha ve been ca ught too. Herein I will a ttempt to a ppra ise the current sta tus of the studies of the TGF-f3 fa mily a nd point out some directions, cha llenges, a nd opportunities for the future.

THE TGF-f3 SUPERFAMILY Prototype Structure The structura l prototype for this gene superfa mily is the protein tha t wa s fi rst isola ted from huma n pla teletsa s TGF-f3 (Assoia n eta l 1 983), cloned froma huma n cDNA libra ry (Derynck etaI 1 98 5), a nd la ter na med TGF-

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THE TGF-f3 FAMILY

599

131 (C heif etz et al 1 987). TGF-f31 i sa di sulfid e-link ed dim er o f two id entical c hain s o f 1 12 amino acid s. Eac h c hain i s synt hesiz ed a s the C- terminal domain of a 39 0 amino acid pr ecur sor that ha s t he c harac teri stic s of a secr etory poly peptid e; it con tain s a hydro phobic signal sequ enc e for tran sloca tion acro ss t he endo pla smic r eticulum and i s glyco sylat ed (D erynck et a 1 1 985 ; si te i s a sequ enc e of four ba sic amino acid s imm edia tely pr ec eding t he bioactiv edomain. Thi s pr ecur sor struc tur e is shar ed by all known memb er s of the su per­ fam ily wi th t he exc eption of t he TGF-f3 4 pr ecur sor, w hic h lack s a d is-

Precursor y

y

y

x

x

x

tc tc

It cc cc It cc cc

ttl ttl

''1!i11!i11I1L: ,in; 'ii_ .,' _

/o

cre!iOn

Latent Forms

activation



Ie cc cc It tt tt

CC

ttl

tt

ttl

Bioactive Dimer

(Platelets) Figure 1

Precursor, latent, and bioactive forms of TGF-PI . The TGF-pl precursor consists (thin line), a pro-reg ion (thick line) and the C-lerminal bioactive domain (box). The approximate locations of the three N-linked glycosylation sites (Y) in the pro-region and the 9 cysteines (C) in the bioactive domain are indicated. The intensity of the shadowing underlining the bioactive domain indicates the degree of amino acid sequence conservation throughout this domain in the other members of the TGF-p superfamily. After secretion, the cleaved pro-region remains associated with the TGF-pl dimer forming a biologically latent complex. In platelets and certain cell lines, the latent complex also contains a I 25-l9 0-kd glycoprotein of unknown function (shadowed). Bioactive TGF-pl is released by disassembly of this complex. of an N-terminal signal sequence

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600

MASSAGUE

cernable signal seq uence (Jako wle w et al 1 988b). The kno wn TGF -f3 · relate d factor s can be gro upe d in fo ur fam il ei s accor din g to the ir de gre { of str uct ural or f unct ional relat ion sh p i (Table I). Mo st of the am in o ac iC seq uence sim ilar ity bet ween fam ily member s is in the C-term inal doma ir of the prec ur sor. The de gree of am in o ac id seq uence ident ity in th is doma ir ran ge s from 25 to 90% bet ween different fam ily member s. The re gio m with h ighe st homolo gy are in dicate d in F igure 1 . At lea st seven of th { cy ste n i e s in th is doma in are con served in all member so f the super fam ily . an dall n n i e cy ste ine sare con serve d in the TGF s-f3 an dthe inh ib in f3 cha in s Except in M uller ian inh ib it n i g sub stance (M IS) (Cate et al 1986), th i� doma in is cleave d to generate a mat ure polypept ide sim il ar in size t c

Table 1

The TGF-p gene superfamily Bioactive dimers

Chromosome name

human

mouse

TGF-pl

19q13

TGF-p2

Iq41

7 I

TGF-p2

TGF-p3

14q24

2

TGF-p3

Gene

composition

TGF-p Family TGF-pl

TGF-p4'

(eDNA only)

TGF-p5b

TGF-p5

homodimer homodimer homodimer

TGF-P1.2

homodimer heterodimer

Inhibin A Inhibin B Aetivin A

a. pA dimer a,p B dimer PA homodimer

Aetivin AB

p A .p B

lnhibin Family a

PA PB

DPP/VG I Family DPP-CC Vg l b vgr- l BMP-2 BMP- 3 BMP-4 BMP- 5 BMP-6 BMP-7 Mullerian Inhibiting Substance Family MIS 19 "

13 2 5 l4,X

dimer

(eDNA only) (eDNA only) (eDNA only) BMP-2 homodimer homo or heterodimers (eDNA only) (eDNA only) homo or heterodimers homo or heterodimers MIS homodimer

b, and' are from chick, Xenopus, and Drosophila, respectively. Chromosomal locations are from

Dickinson et al (1990), Fujii et al (1986), Barton et al (1988) and ten Dijke et al (l988b).

THE TGF- f3 FAMILY

601

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mature TGF- f3l . Most of t he factors in t he family have been isolated as dimers from natural or recombinant sources. T he N-terminal pro-region of a given factor may be conserved between animal species but is usually divergent between different factors (Derynck et al 1 986; Cate et al 1 986). Two potential functions of t he pro-region are to assist in t he folding of t he bioactive domain during synt hesis and, at least in t he case of TGF- f31 , to bind t he mature factor forming a latent complex (see below).

TGFs-f3: Forms, Expression, and Regulation FORMS TGF- f3 is a t erm t hat refers to t he dimeric products of various genes, five to date, identified by isolation of t he proteins or by cDNA cloning. TGF- f3was initially described as an activity produced by retro­ v irally-transformed cells (Roberts et al 1 98 1 ) , TGF s- f3 are e xpre ssed in many normal cells and ti ssues and t hat t his expression is not a unique att ribute of t he t ransfo rmed p henotype. TGF131 has been purified from human and porcine blood platelets (Assoian et aI 1 983), w hic hare t he ric hest source of T GF- f3l(20 mg/kg), from human plac enta (Frolik et a l 1 983) , Porcine platelets (C heifetz et al 1987) and bovine bone (Seyedin et al 1 987) yield TGF- f32 in addition to TGF- f31 . TGF- f31 and 2 were identified in bone based on t heir cartilage-inducing activity, and t hey were named C IF- A and C IF -B before t heir identity wit h T GF- f31 and 2 was known (Seyed in et al 1 985) . activity as a growt h in hibitor (Holley et al 1 980) or as an immuno­ supp resso r (Wrann et al 1 987). TGF- f32 cDNAs have been cloned from human, monkey, and mouse libraries (de Martin et a1 1 987; Madisen et al 1 988; Hanks e t al 1 988; Miller e t al 1 989a). Human TGF- f33 was identified first at t he eDNA level (ten Dijke et al 1988a; Der ynck et a1 1 988) and was subsequently expressed in recombinant form (Graycar et al 1 989; ten Dijke et al 1 990). A c hick embryo c hon­ drocyte cDNA library yielded cDNAs corresponding to TGF- f33 and TGF- f34 (Jakowlew et aI 1 988a,b). TGF- f35 was identified as a eDNA from Xenopus laevis (Kondaia het a1 1 990) and has been puri fie dfrom Xenop us XTC cell c ultures (Roberts et al 1 989). Mammalian TGF-/3 4 and 5 have not been described yet. T he complexity of t his family may be greatly amplified by t he existence of additional members and by t he formation of heterodimers between different TGF- f3gene products co-expressed in t he same cell. T he existence o ft he T GF-fJ I/T GF-fJ2 heterodimer (T GF-fJ1 .2) has been confirmed in porcine platelets (C heifetz et al 1 987). STRUCTURAL CONSERVATION

T he degree of identity between t he five

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602

MASSAGUE

ma ture TGF-p sequenc es ra nges from 64% (TGF-p l vs TGF-P 4) to 82°;; (TGF-p 2 vs TGF-P 4) (Konda iah etal 1 990), but individuall y TGFs-p an extremel y well c onserved. Thus there is > 97% identity between the ma tun TGF-pl sequenc es from va rious ma mmal ia n a nd a via n spec ies (Derynd et a l 1 987; Ja kowl ew et a l 1 988c) , a nd the sa me is true for TGF-p 2 a nd: (Ma disen et al 1 988; la kowl ew et al 1 988a ). Conser va tion is al so evideni a t the genomic l evel . The TGF-/3 1 gene in va rious ma mma lia n spec ies hal a seven-ex on struc ture (Derync k et al 1 987; Va n Obberghen-Sc hilli ng e; a l 1 987) tha t is la rgel y c onserved in other TGF-p genes (Derync k et a 1 988). This c onserva tion suggests tha t the TGFs-p a rose by dup1ica ti or ofa c ommona nc estor. The va rious TGF-p genes, however, a rel oca ted ir sepa ra te c hromosomes in both ma n a nd mouse (Ta bl e 1 ) . Multiplic ity of TGF-p forms a nd sequenc e c onserva tion within ead form through evolution suggest importa nt spec ific roles for eac h of th( TGFs-p . Differenc es a re ma nifested in the pa ttern of expression of th( va rious TGFs-p in vivo (see bel ow) a nd in their a bility to interac t witt different c ell surfac e rec eptors (Cheifetz et a l 1 987). Ac ting on c ulturec c el ls, TGF-p l , 2, a nd 3 often displa y simila rac tivitya nd potenc y (Cheifet. et al 1987; Seyedin et al 1987; Graycar et al 1989), but s how markec differenc es in c erta in ca ses (Ohta et a l 1 987; Ottma nn & P elus 1 988 Tsuna wa ki eta1 1988; Jennings eta1 1 988; Ch eifetz eta I 1 990). Diff erenc e� between the ac tivity of TGF-pl a nd 2 ha vea lso been noted in vivo (Rosa et al 1 988). The high degree of c onserva tion of the individual TGF-t sequences suggests the existence of evolutionary pressure to retain certain

spec ific fea tures of eac h of these fac tors. S uc h fea tures shoul d bec omf a ppa rent from a better c ha rac teriza tion of their individua l ac tivities a nd the resolution of thei r three-di mensi ona l struc tures. EXPRESSION PATTERNS Numerou s c ell types in c ulture express one 01 multiple forms of TGF-p , a tl ea sta t the mRNA l evel (Derync k eta I 1 988), In general , the pa ttern of express ion of the different TGFs-p va ries with eac h c ell typea nd does not a ppea r to be uniforma mong c el ls of the sa me linea ge. Expression ofTGF-p isac tive throughout embryonic devel opment a nd into a dulthood (Heine et a l 1 987; Ra ppolee et a l 1 988; Thompson et a1 1 989; Mil ler eta I 1 989a ). Histoc hemica l local iza tion studies ha ve shown expression of TGF-p l a nd TGF-f3 2 mRNAs or proteins in disc rete regions of ma ny tissues with c ha rac teristic tempora l pa tterns. In the mouse embryo, TGF-p l mRNA is detec ta ble in l ung, intestine, a nd kidney mes­ enc hymes, epithelial struc tures, mega ka ryoc ytes, osteoc ytes, a nd c enters of hema topoiesis (Lehnert & Akhurst 1 988; W li c ox & Derync k 1 988). TGF-f3 2 mRNA is detec ta ble in ga strointestina la nd trac hea l submuc osa e, bl ood vessel s, ski n, ca rtila ge, a nd bone (P el ton et al 1 989). TGF-p

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THE TGF- fJ FAMILY

6 03

immu no staini ng i s hig hi nme sodermal structure si ncludi ng teet h, lary nx, palate , At lea st 1 2 ti ssue s a nd orga ns from adult mou se show e xpre ssio n o f mR NA s for TGF- j3 1 , TGF- j32 , a nd /or TGF -f33 (T homp so n e t al 1 989 ; Miller et a I1 989a,b) ; adre nal corte x, bo ne marrow, cardiac myocyte s, c ho ndrocyte s, re nal di stal tubule s, ovaria n gla ndular cell s, a nd c horio nic cell s o f t he place nta, a nd i n e xtracell ular matrice s o f t he cartilage, ski n, heart , a nd uter us (T homp so n e t al 1 989). T he imm uno hi stological di strib utio n o fa particular TGF- fJ form doe s not alwa ysmatc ht he di strib utio no ft he corre spo ndi ng mR NA, a di screpa nc yt hat could re sult from di ffu sio na nd accumulatio n o f t he protei n awa y from t he site s o f synt he si s, a tra nslatio no ft he mR NA (A ssoia net aI 1 987) , wi tho ther form so fTGF-fJ. CONTROL OF ACTIVITY The e xi ste nce o f mec ha ni sm s t hat tig htly co ntrol t he e xpre ssio n a nd activity o fTGF- fJma ybe e xpected becau se numerou s cell t ype se xpre ssa nd ca nre spo nd to t he se factor s. TGF- f3e xpre ssio na nd activit y are co ntrolled b y (a) reg ulatio n o f TGF -f3 ge ne tra nscriptio n, (b) productio n o fTGF- j3 a s a late nt factor, a nd (c) seque stra tio n o f acti ­ vated TGF s- j3by e xtracellular matri x a nd circula ti ng protei ns. Tra nscriptio n o f t he TGF- fJ I ge ne ca n be stim ulated by p horbol e ster s pre sumabl y via a protei n ki na se C-depe nde nt pat hwa y (Ak hur st et al 1 988), a nd b y TGF- fJl it sel f (Va n Obberg he n-Sc hilli ng et al 1 988). T he 5' (Kim e t al 1989a); o ne promo ter si te loca te d up stream o f the fir st tra n­ scriptio nal start site a nd a seco nd located betwee nt he two start site s(Kim et al 1 989b), a s well a s several tra nscriptio nal i nhibitor y regio ns (Kim et a 1 1 989a, 1 99 0). Bot hpromoter sco ntai ntra nscriptio nal e nha ncer eleme nt s t hat re spo nd to i nductio n by p horbol e ster s a nd TGF- fJ l, or tra nsactiva­ tio n by AP-l (Kim et al 199 0). Ac tiva tio n via t he se eleme ntsi smedia te d b y bi ndi ng o f t he (lu n-Fo s) AP- I comple x (Kim et al 1 99 0). Additio nal p utative p horbol e ster re spo nsive eleme nt sare pre se nt i n t he 3' fla nki ng regio no ft he TGF- fJl ge ne (Scotto et aI 1 99 0). Si nce e xpre ssio na nd activit y o fjun a nd los ge ne s are modulated by numerou s factor s i ncludi ng t heir ow n product s (Sa sso ne-Cor si et al 1 988 ; TGF- fJl (Pertovaara et al 1 989), t he se mec ha ni sm s have t he capacity to fi nel y tune TGF- f31 e xpre ssi o ni nre spo nse to diver se stim uli. Wit h t he e xceptio n o f plate let s, w here TGF- f3 i s stored i n a-gra nule s (A ssoia n& Spor n 1 986), t he TGF s- j3appear to be relea sed from cell s via a co nstitutive secretory pat hway. TGF- fJl , however, i srelea sed from eit her platelet s or cultured cell l ine s a s part o f a n i nactive comple x u nable to

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604

MASSAGuE

interact with cell surface receptors (Lawrence et al 1 985; P ircher et al 1 986). Ex posure to ex treme pH « 4 or > 9), chaotropic agents (sodium dodecyl sulfate, urea) or plasmin in vitro release active TGF- f3 from the latent complex (Lawrence et a1 1 985; Lyons et aI 1 988). The latent complex isolated from human platelets and fi broblasts consists of the mature TGF13 1 dimer plus two TGF-f3 1 pro- region polypeptides disulfide-linked to a glycoprotein of 1 25- 1 60 kd in platelets, or 1 70- 1 90 kd in fibroblasts (Miyazono et al 1 988; W akefield et al 1 988; Kanzaki et aI 1 990). The pro­ region polypeptides are also disulfide-linked to each other. The amino acid sequence deduced from the 1 25- 1 60 kd glycoprotein cO NA contains multiple EGF-like repeats in tandem as the main distinc tive feature (Kanzaki et al 1 990). The funct ion of this protein is unknown at the moment. This protein does not prevent binding of activated TGF-f3 1 to c ells, has no detectable proteolytic activity, and does not appear to bind activated TGF-f3I , or to be related to the TGF- f3-binding proteoglycan, betaglycan (see below). Studies with cells that overex press a transfected TGF-f3 1 gene, however, indicate that association of mature TGF-f3 1 with the pro-region is sufficient to retain this factor in the latent state (Gentry et al 1 988). Glycosylation and dimerization of newly translated TGF-f3 1 precursor are followed by cleavage of t he mature domain that continues to interact with the pro­ region aft er release from the cell (Gentry et al 1 988). The pro-region appears to be essential for the correct folding of TGF- f3 1 during synthesis (Gray & Mason 1 990). The TGF-f3 1 pro- region contains mannose 6p hosp hate (P urchio et al 1 988) as well as the ar g-gly-asp (RGO ) sequence that in fibronectin, vitronectin, laminin, and other cell adhesion molecules recognizes certain adhesion receptors of the integrin class (Ruoslahti & P ierschbacher 1 987). The TGF- f3 1 pro-region can bind to cell surface mannose 6-phosphate receptor s (Kovacina et al 1 989), but it i s not known whether the RGO sequence can mediate binding of proTGF-I3 s to integrins, or whether binding mediated by RGO or mannose 6-phosphate can lead to activation of latent TGF-f3l . The precise mechanisms that acti vate latent TGF-f3 in vi vo are also unknown. Endothelial cell cultures can activate latent TGF- f3, but only when cells are in contact with vascular pericytes (Antonelli-Olridge et al 1 989; Sato & Rifkin 1 989). Evidence suggests that the proteolytic action of plasmin or cathepsin 0 on the TGF­ f3 1 pro-region (Lyons et al 1 988; Sato & Rifk in 1 989), the removal of carbohydrate residues in this region (Miyazono & Heldin 1 989), and the action of acidic microenvironments in sites of wound healing and bone resorption might contribute to activate latent TGF-f3 1 in vivo. Once released from the latent complex , active TGF-f31 can be bound by various ex tracellular matrix components and serum proteins. Clearance

THE TGF- fJ FAMILY

6 05

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o f circulati ng activated TGF- fJ i s e xtremely rapid (< 3 mi n; Coffey et al 1987) a nd b indi ng to tt2-macroglobuli n mig ht be i nvolved i nt hi s proce ss (O 'Co nnor-McCourt & Wakefield 1 987). TGF- fJca naccumulate i ni nter­ sti tial matrice s(Thomp so net a I1 989). Hig h a ffinity bi ndi ng o f TGF-p to t he core protei n o f t he proteoglyca n, betaglyca n (A ndre s et al 1989), or lower affi nity i nteractio nswit h abu nda nt matri xcompo ne nt s, mig ht pro­ tect TGF- fJ from degradatio n, su stai ned relea se mec ha ni sm , or TGF-p cleara nce sy stem.

Inhibins and Activins I nhibi ns a nd activi ns are dimeric polypeptide s i nitially i solated from ovaria n foll ci ular fluid ba sed o n their ability to modula te t he productio n o f follicle- st m i ulati ng hormo ne (FSH) from pituitary cell s(Li ng et aI 1 985). T he i nhibi ns are compo sed o f an

The transforming growth factor-beta family.

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