Transforming growth factor-s (TGF-s) ()belong to a family of multifunctional cytokines that regulate cell proliferation, differentiation, extracellular matrix formation, and immunosuppression (1, 2, 3, 4) . TGF-s exert their pleiotropic effects through binding to specific cell surface receptors. Three major classes of receptors for TGF-s have been identified by chemical cross-linking to I-TGF-s. Those are type I (TR-I, 55 kDa), type II (TR-II, 75 kDa), and type III (TR-III, 280 kDa). Previous studies on chemically mutagenized mink lung epithelial cell lines suggested that the type I and type II receptors interact with each other and both receptor types are required for mediation of biological responses to TGF-1(5) .

Recently a number of receptors for different members of the TGF- superfamily have been molecularly cloned(3, 4, 6, 7) . TR-III has a short cytoplasmic region and probably facilitates TGF- effects by presenting ligand to the signaling receptors(8) . TR-I and TR-II are serine/threonine kinases directly involved in TGF- signaling. The function and role of each type of the receptors, however, are distinct. TR-II binds ligand without TR-I whereas TR-I requires TR-II to bind ligand(9) . TR-II determines ligand specificity(10) , and TR-I specifies cellular responses(11) . A model of ligand-induced activation of the receptors has been proposed (12) . TR-II kinase is constitutively active and autophosphorylated. Upon ligand binding, TR-II associates with and phosphorylates TR-I. This transphosphorylation presumably activates TR-I kinase resulting in the phosphorylation of downstream substrates that are still unknown.

It has been shown that the TGF- receptors interact both physically and functionally. In I-TGF-1 chemically cross-linked cells, antibodies specific for type I or type II receptor precipitated both type I and type II receptors(13, 14) . Anti-type II receptor antibodies also precipitated type III receptor(14) , showing that TR-I, TR-II, and TR-III form heterooligomeric complexes in the presence of ligand. Evidence suggests that TR-II and TR-III can exist as homooligomers both in the absence and presence of TGF-1 (15, 16) . Two-dimensional gel analysis of ligand-bound receptor complex indicates that TR-I and TR-II may exist in a tetramer containing two molecules of TR-I and TR-II(17) . More recent studies indicate that the association of TR-I with TR-II is ligand-dependent; however, the possibility that these receptors may have a low intrinsic affinity for each other was not excluded(12) .

The TGF- superfamily comprises over 20 different members. The type II receptors for two family members, activin (ActR-IIA) and TGF-1, were initially cloned through expression screening(18, 19) . Another mammalian type II receptor for activin (ActR-IIB)(20) , the Drosophila activin type II receptor (Atr-II)(21) , and the Müllerian-inhibiting substance (MIS) type II receptor(22, 23) were subsequently isolated. The protein product of the Caenorhabditis elegansdaf-4 gene, responsible for the inhibition of dauer larva formation, was shown to be a distinct type II receptor that binds human BMP-2 and -4(24) . However, type II receptors for other ligands in the TGF- superfamily have not been identified as yet.

Here we report the identification of a novel putative type II serine/threonine kinase receptor through its interaction with the cytoplasmic region of TR-I. We further show that the cytoplasmic regions of several of the type I and type II receptors heterodimerize in the yeast two-hybrid system while type I-type I and type II-type II interaction were not observed.

EXPERIMENTAL PROCEDURES

Screening

Plasmids

Interaction Assay

Northern Blot

RESULTS

Proteins that interact with TR-I appear to play an important role in TGF- signaling. We used a modified version of the two-hybrid system, the interaction trap screen developed by Brent and co-workers(25, 26) , to identify proteins that interact with the cytoplasmic region of the rat TR-I, R4(27) . EGY48, the yeast host strain, was first transformed with the -galactosidase reporter gene, pSH18-34, and the TR-I bait, pEGR4, plasmids followed by introduction of the HeLa cell expression cDNA library as a prey. One million five-hundred thousand transformants were screened. Primary yeast colonies that grew on selection media were tested for leucine auxotrophy and -galactosidase activity, and 17 positive clones were isolated. One class of the final clones encodes FKBP12, a binding protein for FK506 and rapamycin. ()One of the other clones, CL130, had an insert of 1.5 kb, and partial sequencing revealed that the cDNA encoded a putative serine/threonine kinase receptor. Rescued CL130 plasmid was reintroduced into EGY48 with the reporter gene and the TR-I bait, and the interaction was reproduced (data not shown).

The sequence of CL130 was most homologous to the cytoplasmic region of the activin receptor type IIA (data not shown) but lacked corresponding transmembrane and extracellular regions. To obtain the full coding region, human kidney cortex and human placenta libraries were screened with CL130 as a probe. Twelve clones were isolated and one of them, CL4-1, with an insert of 3.3 kb was found to contain the entire coding region. Nucleotide sequencing of CL4-1 revealed an open reading frame of 3114 base pairs, encoding 1038 amino acids. The nucleotide and deduced amino acid sequence of CL4-1 are shown in Fig. 1A. An in-frame stop codon was found at -21 to -19 in the 5`-untranslated region. The predicted starting ATG codon is followed by a stretch of hydrophobic amino acids that is assumed to be a signal peptide. Another hydrophobic region, a putative transmembrane region, was identified between amino acids 151 and 174. Three potential N-glycosylation sites were found in the extracellular region. The calculated molecular mass of the protein is 115,317 daltons.

Figure 1: DNA sequence and protein structure of T-ALK. A, nucleotide and deduced amino acid sequence of T-ALK. Two hydrophobic regions (signal peptide and transmembrane region) are underlined. Three potential glycosylation sites are indicated with asterisks. The putative kinase domain is shown between brackets. Protein sequence shared by CL130 and CL4-1 is shown between arrowheads. B, peptide sequence alignment of type II receptors. hActR-IIA, human type IIA activin receptor(18) ; mActR-IIB, mouse type IIB activin receptor(20) ; rMISR-II, rabbit Müllerian-inhibiting substance receptor(23) ; hTR-II, human type II TGF- receptor(19) ; dAtr-II, Drosophila type II activin receptor(21) ; daf-4, C. elegansdaf-4 (24). Conserved amino acids are shown in uppercase. Part of the tail region (amino acids 699-1038) of T-ALK is omitted. Romannumerals indicate the subdomains of the conserved kinase region. C, schematic representation of T-ALK, type II activin receptor, and type I TGF- receptor. Cysteine residues are shown with verticalbars. TM represents transmembrane region. The GS domain is a region with a series of serine and glycine residues, which is characteristic of type I receptors(11) . D, comparison of CL130 and CL4-1. DNA and peptide sequences are shown. The DNA sequence between 1586 and 2867 (1280 bases) of CL4-1, shown in lowercase, is missing in CL130.

The coding region of CL4-1 was used to search a data base (the BLAST network service at NCBI). The most highly related molecule was the activin receptor type IIA, followed by the activin receptor type IIB, anti-Müllerian hormone receptor, and TR-II (data not shown). The type I receptors had less similarity. These results suggest that CL4-1 encodes a novel type II receptor, and we named this receptor T-ALK (type II activin receptor-like kinase). The amino acid sequence of T-ALK was compared with other type II receptors using the combination of the MACAW program (28) and manual alignment (Fig. 1B). T-ALK has 6 single cysteines and one stretch of 4 cysteines (cysteine box(11) ) between the signal peptide and the transmembrane region. Most of these cysteines are conserved among the type II receptors whereas their arrangement is different from that of the type I receptors. T-ALK has a spacer region between the transmembrane region and the kinase region. The spacer region is variable among the type II receptors. T-ALK lacks the GS domain that is characteristic to the spacer region of the type I receptors(11) . The kinase region is highly conserved with other type II receptors. One of the most distinct features of T-ALK is its long tail region following the kinase region. Most of the type II receptors have a short tail region that ranges from 20 to 50 amino acids. Only daf-4 has a relatively long tail with approximately 140 amino acids. In contrast, the tail of T-ALK has about 430 amino acids that comprises approximately 40% of the entire coding region (Fig. 1C). Data base search with the tail sequence did not give any significant homologous proteins. Comparison between CL130 and CL4-1 revealed that CL130 contains the entire kinase region and lacks most of the tail region (Fig. 1, A and D), probably due to alternative splicing. The coding frame of CL130 after the deletion is different from that of CL4-1, resulting in a premature stop.

To determine the tissue-specific expression of T-ALK, Northern blot analysis of poly(A) RNA from different tissues was performed. Three distinct messages of 11, 8, and 5 kb were detected in every tissue examined. The 11-kb message was highly expressed in heart and liver (Fig. 2). The relative abundance of the three transcripts varied from tissue to tissue. This may reflect tissue-specific processing of mRNA.

Figure 2: Northern blot of T-ALK mRNA. A blot with mRNA (2 µg/lane) from various human tissues (Clontech) was probed with T-ALK cDNA. The sizes of molecular mass markers are indicated in kb.

From the amino acid sequence alignment, T-ALK is most likely to be a novel type II serine/threonine kinase receptor. We cloned T-ALK through its interaction with TR-I. Tsk 7L(29) , the mouse homolog of ALK-2/SKR-1/ActR-IA, and TR-II interact with each other at their cytoplasmic regions in the yeast two-hybrid assay as well as in immunoprecipitation with mammalian cells (data not shown). These two independent results indicate that the heterodimerization of the cytoplasmic regions may be more universal and apply to other combinations of the type I and type II receptors. To address this hypothesis, we tested the interaction between the type I and type II receptors more thoroughly. The bait and prey plasmids that express the cytoplasmic region of Tsk 7L, TR-I, TR-II, and T-ALK (CL130) were constructed. All possible combinations of these plasmids were tested in the yeast assay. A unique feature of the interaction trap system is that the expression of the prey protein is under the control of a derivative of the GAL1 promoter(25, 26) . Therefore the interaction detected in this assay is significant only when it is galactose-dependent, which, in turn, indicates that the observed interaction is explicitly dependent on the prey proteins. Any combination between the type I and type II receptor showed galactose-dependent interaction both in the -galactosidase and leucine auxotrophy assay (Table 1). In contrast, neither combination of type I with type I nor type II with type II gave positive results. Thus, the data indicate that the cytoplasmic regions of the serine/threonine kinase receptors do heterodimerize but not homodimerize.

DISCUSSION

To detect protein-protein interaction in the two-hybrid assay, it is essential for both bait and prey proteins to localize in the yeast nucleus(30) . This is one of the reasons we chose the cytoplasmic region of TR-I as the bait. The extracellular and transmembrane region might affect the nuclear localization of the bait proteins. We have not found any other report of cloning of a transmembrane receptor through the two-hybrid screening. Our results suggest that the two-hybrid screening can be applicable to isolation of transmembrane proteins as well as cytoplasmic proteins.

We cloned a novel serine/threonine kinase receptor, T-ALK, through the two-hybrid screening system with the cytoplasmic region of TR-I as a bait. T-ALK has several features characteristic to type II receptors. First, the activin, anti-Müllerian hormone, and TGF- type II receptors showed high scores in a homology search of a data base with the whole coding sequence of T-ALK while type I receptors shared less homology. More specifically, cysteine residues in the extracellular region of T-ALK have an arrangement common to type II receptors. The spacer region does not have the GS box that is shared by type I receptors. Therefore T-ALK is likely to be a novel type II serine/threonine kinase receptor. T-ALK is highly expressed in heart and liver. In contrast, mouse TR-II is abundant in lung, uterus, and skeletal muscle(31) . The expression of mouse ActR-IIA is high in brain and kidney(32) . C14, a putative rat Müllerian hormone type II receptor, is exclusively expressed in testis and ovary(23) .

T-ALK was isolated through its interaction with TR-I. Recently it was shown that TR-II can phosphorylate TR-I(12) , suggesting that the cytoplasmic region of TR-II interacts with that of TR-I. Our results support this idea. The association in mammalian cells with the full-length receptor, however, was ligand-dependent. In our system, we used the cytoplasmic region of the receptors. One possibility is that the cytoplasmic region of both receptors without the extracellular and transmembrane regions could be constitutively active. The cytoplasmic region of rat TR-I fused to glutathione S-transferase was shown to have autophosphorylation activity in vitro(27) , whereas TR-I was not phosphorylated in the absence of TGF- in vivo(12) . The cytoplasmic region of TR-II was also shown to have autophosphorylation activity in vitro(19) . This is similar to the protein product of the v-erbB oncogene, which is the truncated form of the epidermal growth factor receptor with a constitutively active kinase(33) . A second possibility is that the interaction in the yeast system may reflect the ligand-independent low intrinsic affinity between the receptors (12) since the two-hybrid system is a remarkably sensitive assay for protein-protein interaction as compared with co-immunoprecipitation (34) . Interestingly, dimerization within the same receptor class was not detected. Recently homomeric interaction of TR-II both in the presence (15, 17) and absence (15, 16) of ligand was reported. The reason for the discrepancy between these results and our results is not clear. The extracellular region without ligand may be sufficient to mediate the TR-II homodimerization. In one of the reports, however, it was shown that the cytoplasmic regions of TR-II interact with each other(16) . In mammalian cells, multimeric interaction such as type II binding type I-type II heterodimer via endogenous receptors could happen. The existence of tetramers of TR-I and TR-II has been suggested(17) . In contrast, yeast cells do not have endogenous TGF- receptors.

Activin and TGF- type II receptors were cloned by expression cloning using COS cells(18, 19) . The daf-4 gene was isolated through a genetic approach(24) . C14, the rat MIS receptor, was identified by differential screening between testosterone-treated Sertoli cells and untreated cells(22) . Most of the other receptors have been cloned by homology screening. Cloning of type I receptors by expression screening seems to be difficult since type I receptors require type II receptors to bind ligand(9) . Here we present a novel strategy to isolate serine/threonine kinase receptors. Type I and type II receptors interact with each other in the yeast assay. Therefore the two-hybrid screening would be another useful method to isolate both type I and type II serine/threonine kinase receptors. Considering the large number of ligands in the TGF- superfamily(3, 4, 6, 7) , it is likely that a large number of receptors in this class remains to be identified.

FOOTNOTES

*

This work was supported in part by National Institutes of Health Grant CA 42572 (to H. L. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank(TM)/EMBL Data Bank with accession number(s) U20165[GenBank].

§

To whom correspondence should be addressed. Tel.: 615-322-2134; Fax: 615-343-4539.

()

The abbreviations used are: TGF-, transforming growth factor-; ALK, activin receptor-like kinase; T-ALK, type II activin receptor-like kinase; MIS, Müllerian-inhibiting substance; kb, kilobase(s); X-gal, 5-bromo-4-chloro-3-indoyl -D-galactoside.

()

M. Kawabata, H. Yamashita, M. E. Engel, C.-H. Heldin, K. Miyazono, and H. L. Moses, submitted for publication.

ACKNOWLEDGEMENTS

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				H. Nishitoh, H. Ichijo, M. Kimura, T. Matsumoto, F. Makishima, A. Yamaguchi, H. Yamashita, S. Enomoto, and K. Miyazono Identification of Type I and Type II Serine/Threonine Kinase Receptors for Growth/Differentiation Factor-5 J. Biol. Chem., August 30, 1996; 271(35): 21345 - 21352. [Abstract] [Full Text] [PDF]