Molecular Biology Reports 16: 241-248, 1992, 9 1992 Kluwer Academic Publishers. Printed in Belgium.

241

Identification and typing of members of the protein-tyrosine phosphatase gene family expressed in mouse brain Jan Schepens, Patrick Zeeuwen, B6 Wieringa & Wiljan Hendriks*

Department of Cell Biology & Histology, University of Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands (* corresponding author) Received 17 February 1992; accepted in revised form 24 March 1992

Key words: mouse brain, protein evolution, protein-tyrosine phosphatases, signal transduction

Abstract

Protein-tyrosine phosphatases (PTPases) form a novel and important class of cell regulatory proteins. We evaluated the expression of PTPases in mouse brain by polymerase chain amplification of cDNA segments that encode the catalytic domains of these enzymes. Degenerate primer pairs devised on the basis of conserved protein motifs were used to generate a series of distinct PCR-derived clones. In this way, murine homologues of the human PTPases LRP, PTPfl, PTPb, PTP8 and LAR were obtained. Corresponding regions in their catalytic domains were used to reveal the evolutionary relationships between all currently known mammalian PTPase protein family members. Phylogenetic reconstruction displayed considerable differences in mutation rates for closely related PTPases.

Introduction

Tyrosine phosphorylation is used to modulate virtually every aspect of cellular function including cell cycle regulation, gene transcription and signal transduction [1]. The addition and removal of phosphate groups on tyrosine residues is thought to be tightly controlled by the opposing actions of protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (protein-tyrosinephosphate phosphohydrolase, EC 3.1.3.48; PTPases). Thus far, research has been mainly concentrated on the role of PTKs, not in the least because a number of oncogene products were shown to have tyrosine kinase activity [2]. Evidence for an equally important role of PTPases in cell growth and differentiation has been obtained much more recently. PTPases were first identified

when the human placental PTPase 1B was isolated, purified, and shown to be homologous to a repeated sequence in the cytoplasmic domain of the leukocyte cell-surface protein LCA (also known as CD45 or Ly-5) [3]. This finding had two important implications: first, unlike PTKs which are related to Ser/Thr kinases, it seemed that PTPases were unrelated to any of the Ser/ Thr protein phosphatase families [4]; second, the receptor-type structure of LCA suggested that the PTPases represent a novel, independent class of signalling molecules. Many, mostly human, PTPases have now been cloned using either low-stringency hybridization or polymerase chain reaction (PCR) techniques [5-29] based on the strong sequence conservation within their catalytic domain, which spans some 300 amino acid residues. PTPases can be

242 divided into three classes based on their overall structures [8]. Class I contains the cytoplasmic molecules with one phosphatase domain; class II contains the transmembrane molecules with one cytoplasmic phosphatase domain; and class III contains the transmembrane molecules with two cytoplasmic phosphatase-like domains. In spite of the increase in structural information on PTP ases, still relatively little is known about their function. The best studied PTPase thusfar is LCA which plays an essential role in the stimulation of T cell proliferation (reviewed in [30]). Other PTPases, in contrast, were shown to play a role in limiting growth responses [31-33]. Moreover, it was demonstrated that administration of phosphatase inhibitors may result in a transformed cellular phenotype [34]. Recently, it has been shown that the dephosphorylation of cdc2 on tyrosine, an essential step in the cell cycle controlling entry into mitosis, is due to intrinsic PTPase activity of the cdc25 protein [35-37]. This provides perhaps the clearest demonstration of PTPase impact on regulation of cell growth. In addition, the striking homology between the extracellular domains of some receptor-type PTPases with that of cell-adhesion receptors like N-CAM suggests an important role for PTPases in developmental processes like differentiation, homing and sorting [5, 7, 8, 26]. This is now supported by recent findings in Drosophila where PTPases seem to be involved in axon outgrowth and guidance [27, 28]. To study the role of the PTPase family in mouse development, we set out to clone murine representatives of the various PTPases using PCR. In addition, an inventory of the mammalian PTPase family was made. Our findings form a starting basis for further determination of PTPase function in an organismal context.

domains in PTPases. Oligonucleotide 1 (n -- 576) was derived from a compilation of PTPase protein sequences that in LCA is D F W R M I W E [38-41] and consisted of 5'-GA(C/T)TT(C/T)

TGG(A/C)(A/G/T)(A/G)ATG(A/G)T(A/C/T) TGG(G/C)A-3'. Likewise, oligonucleotide 2 (n= 512) was derived from the compilation of PTPase sequences that in LCA is complementary to the region encoding H C S A G V G R [38-41] and consisted of 5'-C(G/T)CCC(A/T)(A/G)C(A/G/ C/T)CC(A/T)GC(A/G/C/T)CT(A/G)CAGTG-3 '

Polymerase chain reaction (PCR) DNAs of mouse brain (Stratagene Inc.) and bovine lens c D N A [42] phage libraries were used as a template in PCR reactions. Primers 1 and 2 (final concentration of 7 ng/#l) were added to a 100 #1 reaction mixture containing 20 m M TrisHCI (pH = 8.4), 50 mM KC1, 2.5 mM MgC12, 0.01 ~o BSA, all four dNTPs (each at 250 #M), 2 units Taq Polymerase (Perkin Elmer Cetus), and 10 ng of phage DNA. Thirty-five cycles were performed on a Perkin Elmer Thermal Cycler; each cycle involved an incubation at 94 ~ for 0.5 min, at 37 ~ for 0.5 min and at 72 ~ for 1 rain. The PCR products were treated with proteinase K as described by Crowe et al. [43]. After DNA end-repair using Klenow (Large Fragment) D N A Polymerase and a kinasing reaction with T4 Polynucleotide Kinase, the products were analyzed on a 1.5 ~o low-melting-temperature agarose gel. Fragments of 350-400 basepairs were excised and subcloned into the SmaI site of pBlueScript according to standard protocols [44].

Sequencing and computer analysis Materials and methods

Synthesis of oligonucleotides Degenerate oligonucleotide primers 1 and 2 were chosenusing consensus sequences for highly conserved amino acid stretches within the catalytic-

Sequences were determined using the doublestranded D N A dideoxy sequencing method [45 ]. D N A sequence gel readings were recorded, compared, edited, and assembled using the IGSUITE 5.35 package (Intelligenetics, Inc., Mountain View, California). Amino acid sequences

243 were manually aligned using the program SALE, written by Dr. J. Leunissen ( C A O S / C A M M Center, Nijmegen, The Netherlands) and run on a VAX 11/780 computer. Evolutionary reconstruction was done using the program F I T C H as supplied in the phylogeny inference package PHYLIP, distributed by Dr. J. Felsenstein (University of Washington, Seattle). F I T C H uses distance matrices to construct trees without allowing negative branch lengths.

Results

PCR amplification of PTPase cDNAs To isolate murine c D N A clones encoding PTPases, we designed degenerate oligonucleotide primers based on sequences conserved in most known PTPases [8]. Using these primers, P C R amplification of PTPase sequences should yield a major product of 350-400 basepairs representing the core region of the catalytic phosphatase domain. Eighteen c D N A clones with the appropriate insert length were isolated from an experiment using mouse brain c D N A as template in the amplification reaction. Upon analysis, these clones were found to represent 8 different PTPase domain sequences. Computer-assisted comparison with known PTPases revealed that one sequence (mLRP-2) was identical to the second

phosphatase domain of LRP [10]. This receptortype PTPase is the murine homologue of HPTP~ [8] (also called R-PTPase ~ [13] or H L P R [15]) in man. The sequences in mLAR-1 and mLAR-2 were homologous to the human and rat LAR [5, 29] phosphatase domains 1 and 2, respectively (Figs. 1 and 2). The sequences in mPTPb-1 and mPTPe-1 were murine homologues of the first phosphatase domain of human H P T P b and HPTP~ [8] (Fig. 2). One sequence, mPTP/~, represents the murine homologue of the single phosphatase domain of HPTP/~ [8] (Fig. 2). Finally, two sequences displayed only weak resemblance to any of the known PTPases and will be discussed elsewhere (data not shown). In a parallel experiment, PTPase cDNAs were amplified from bovine lens c D N A [42] using the same primer set. Resulting clones were analyzed and found to contain a sequence representing the first phosphatase domain of the bovine homologue of LRP (Fig. 2). For reasons of completeness, this sequence will be included in the comparison described below.

Comparison of mammalian PTPase domains Over the past two years, rapid progress has been made in the cloning and identification of PTPase genes. This has led to the confusing situation that for many PTPases several different names are

H N S T I I V M L T K L R E M G R E K C H Q Y W P A E CACAATTC CACCATCATCGT CATGCTGACCAAG CTTCGGGAGATGGGCAGGGAGAAATGTCACCAGTACTGGCCAGCAGAG ........................................................... C .....................

81 5608

mLAR-2 hLAR

R S A R Y Q Y F V V D P M A E Y N M P Q Y I L R E F K CGCTCCGCTCGCTATCAGTACTT CGTTGTTGACCCGATGGCTGAGTACAACATGCCCCAGTATATTCTGCGTGAATTCAAA ..... T . . . . . . . . C . . . . . . . . T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . . . . . . . . G ..... G

162 5689

IELAR -2 hLAR

V T D A R D G Q S R T I R Q F Q F T D W P E Q G V P K GTCACAGACGCCCGGGATGGGCAGTCAAGGACAATC CGACAGTTCCAGTTTACAGACTGGC CAGAGCAAGGAGTACCCAAA ..... G . . T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G . . . . . . . . . . . C . . . . . . . . . . . . . . . . . G . . C . . G ..... G

243 5770

mLAR-2

T G E G F I D F I G Q ACAGGTGAAGGCTTCATCGACTTCATCGGGCAGGTG

mT.AR-2

hLAR

.....

C..G..A

.....

T ....................

V

H K T K E Q F G Q D G P I T V CACAAGACAAAGGAGCAGTTTGGCCAGGATGGGCCCATCACGGTG T ..... C .............. A ........... T .........

324 5851

Fig. 1. Nucleotide sequence of mLAR-2. For the corresponding region (the second phosphatase domain) of the human LAR cDNA sequence [5] only the bases that are different are shown below the murine sequence. The deduced amino acid sequence for mouse, indicated in the one-letter code above the nucleotide sequence, is identical to that of human LAR.

244 i0

20

30

40

50

60

hLCA mLCA rLCA hPTP6 mPTP6 hLAR mLAR rLAR hPTP~ mPTP~ hPTP( mPTP( hLRP mLRP bLRP hPTP 7 hPTP~ hPTP~ mPTP~ hTCPTP rTCPTP hPTPIB rPTPIB hPTPIC hMEG hPTPHI rSTEP

70

80

90

i00

ii0

120

hLCA mLCA rLCA hPTP6 mPTP6 hLAR mLAR rLAR hPTP~ mPTP~ hPTP( mPTPE hLRP mLRP bLRP hPTP 7

hPTP~

hPTP~ mPTP~ hTCPTP rTCPTP hPTPIB rPTPIB hPTPIC hMEG hPTPHI rSTEP

Fig. 2. Alignment of deduced amino acid sequences from PCR-derived mouse brain PTPase c D N A clones and corresponding regions in other mammalian PTPases. h: human; m: murine; r: rat; b: bovine sequence. The number above the alignment indicates the relative position within the region which starts immediately after the sequence DFWRM(I/V)W(E/D) found in most PTPase domains. The region ends just before the stretch that contains the essential cysteine residue (HCSAG(V/I)GR in the catalytic domain). For the receptor-type PTPases, only the first phosphatase domain sequence is used for the comparison and

245 used in the literature. In addition, only once a thorough analysis of the evolutionary relationship of PTPases, based on early sequence data, has been made [8]. We have tried to clarify the relation between the many different mammalian PTPases by making an alignment of the deduced amino acid sequences for our murine clones and phosphatase domains in the PTPases currently known. For the receptor-type PTPases, only the first phosphatase domain sequence is used for the comparison, in accordance with the earlier study by Krueger et al. [8]. Moreover, only the region corresponding with the amplified segment in our experimental set-up was included. In Table 1, an overview is given of the mammalian PTPase types currently identified, including their names and source(s). This shows that up to now 15 distinct types of PTPases have been identified in humans, mice and rats. Within the aligned PTPase core region, 11 amino acid positions are totally invariant (indicated by asterisks in Fig. 2), while many other amino acid positions are highly conserved (shown on a grey background in Fig. 2). The sequence alignment was used to reconstruct the evolutionary history of this protein family. A possible phylogenetic tree was constructed based on a distance matrix using the unweighted pair-group method [48]. This tree (Fig. 3) is in fairly good agreement with the results of Streuli and coworkers [8]. Our analysis suggests that the PTPT/~ group was the first to branch off from the class III PTPase subfamily whereas in ref. [ 8 ] this event is preceded by the branching off of the LCA and the LRP/PTPe groups. This minor discrepancy can be explained by the fact that in the current study a smaller segment and a larger group of sequences was used. Moreover, the mutational

rSTEP ~ r : hLCA

"2 hPTP~ mPTP~

I '

/ I F hPTP/= r mPTP# j'~ hPTP~ L__ mPTP~

-I

rhLRP

hPTP7 hPTPJ"

E hPTPg mPTPB

E TCPTP rTCPTP

F hPTP1B f

~ rPTP1B hPTPIC I 01

0.2

hMI:'G hPTPH1 0.3

0.4

0.5

Fig. 3. A possible phylogenetic tree of the mammalian protein-tyrosine phosphatase gene family. This unrooted tree was constructed using the program FITCH, performing global rearrangements to verify the obtained topology. Changes in sequence input order did not alter the tree topology. The scale for branch lengths (bottom) is in minimal mutational distances per amino acid residue.

distances between the early branch points in class III divergence are rather small making an interpretation of the sequence of events rather difficult.

the number of gaps introduced was kept to a minimum. The gap around position 70 was introduced between amino acid residues of which the corresponding triplets are located in different exons of the LCA gene [46, 47], the other two gaps are arbitrarily chosen. The positions where all sequences share an identical amino acid are indicated by asterisks and the positions where 12 or more out of 15 PTPase types share identical residues are shown on a gray background. Mutations between orthologous sequences as compared to the human sequence are in bold face. As the sequences of mLRP and rLRP over the region used here are fully identical, only mLRP is shown. For sequence references see Table 1.

246 Table 1. Mammalian sequences.

protein-tyrosine

Code

Organism

Original name

Reference

hLCA

Human

mLCA

Mouse

rLCA

Rat

hPTP3

Human

mPTPb hLAR

Mouse Human

mLAR rLAR

Mouse Rat

hPTP/~ mPTP# hPTPe

Human Mouse Human

mPTP~ hLRP

Mouse Human

mLRP

Mouse

rLRP bLRP hPTP ?

Rat Bovine Human

hPTP ~

Human

hPTP B

Human

mPTP/~ hTCPTP

Mouse Human

rTCPTP hPTP1B

Rat Human

rPTP1B hPTP1C hMEG hPTPH1 rSTEP

Rat Human Human Human Rat

T200 PTP191-3* LY-5 Y200 pLC-1 5B3B* HPTPb PTP191-10* mPTPS-I* LAR PTP191-5/30* mLAR-I* rLAR 5A3B2* hRPTP/~ mRPTP# HPTPe PTP191-36* mPTPe-I* HPTPe RPTPase e HLPR PTP191-2* LRP R-PTP-ct 5A3Bl* bLRP-1 H PTP y RPTPase 7 PTP191-13* HPTP ( RPTPase B HPTPB PTP191-1* mPTP~ T-cell PTPase PTP191-22* PTP-S PTP1B PTP191-17* PTPase-1 PTP1C PTPase MeG PTPH1 STEP

[40] [14] [39] [411 [38] [23] [8] [ 14] This paper [ 5] [ 14] This paper [29] [23] [26] [26] [8] [14] This paper [8] [13] [15] [ 14] [ 10] [ 12] [23] This paper [ 8] [13] [14] [8] [13] [8] [14] This paper [6] [ 14] Acc. no X58828 [3] [ 14] [9] [24] [ 21 ] [22] [25]

phosphatase

Two published sequences were not included (PTP191-33 [ 14] and novel-2 [21]) because they did not comprise the complete region used for the alignment shown in Fig. 2 and were not identical to any of the PTPase sequences listed above. * PCR-derived fragments.

Discussion

To obtain probes to study the expression of PTPases in mouse brain, we used a PCR approach that is based on the existence of conserved sequences within this gene family. The analysis of the obtained sequences was extended to a thorough evaluation of all current mammalian PTPase sequences (Table 1). As mentioned previously, PTPases can be divided into three classes based on their overall structures [8]. This classification is consistent with the phylogenetic tree (Fig. 3) since the type I (PTP1B, TCPTP, PTP1C, PTPH1, and MEG), type II (PTPfl), and type III (LCA, LAR, LRP, PTP~,, PTPb, PTPe, PTP(, and PTP/~) are separately clustered. The only ex ception is STEP, a cytoplasmic PTPase, which is grouped with LCA. This can be explained by the limited number of residues that could be included in the alignment in combination with the rather large mutational distance of STEP to other PTPases. Phylogenetic reconstructions using a larger alignment area indeed result in the clustering of STEP with the other class I PTPases (data not shown). The radiation of the classes I and III into their respective subgroups nicely coincides with the divergence in structural features of the PTPases outside the catalytic domain region. For instance, MEG and PTPH1 are grouped (Fig. 3) and both do have an N-terminal segment that displays sequence homology to domains in the cytoskeleton-associated proteins band 4.1, ezrin, and talin that direct their association with proteins at the interface between the plasma membrane and the cytoskeleton [21, 22]. Also, the class III PTPases that contain an extracellular domain composed of both immunoglobulin-like and fibronectin type III domains, a feature commonly seen among cell-adhesion receptors [49], form a separate cluster (LAR, PTPb, and PTP#). Within the different subgroups another interesting observation can be made. Because the branch lengths in Fig. 3 reflect the evolutionary distance, a considerable difference in mutation rate since the primate-rodent divergence is displayed between different PTPases. For example, PTPb seems to

247 evolve at a speed about four times faster than that of its close relative LAR PTPase. The same holds true for PTPe versus LRP. The explanation for this difference in evolutionary selective pressure on closely related PTPases will have to wait until much more data on the biophysical role and biochemical interactions of the individual PTPase members are at hand. As a result from ongoing research we may expect that soon much more members than the 15 discussed here will be typed for the PTPase family. P C R techniques as used here, or approaches involving more elaborate functional cloning schemes may extend the PTPase family to a size similar to that of its counterpart, the PTK family [50]. Regular updates on the tissue expression and the evolutionary relationships as presented here may contribute to provide a background for the understanding of the functional role of all these proteins in cell growth and differentiation.

Acknowledgements We thank Dr. W.W. de Jong for critical reading of the manuscript. The use of the services and facilities of the Dutch C A O S / C A M M Center are gratefully acknowledged.

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Identification and typing of members of the protein-tyrosine phosphatase gene family expressed in mouse brain.

Protein-tyrosine phosphatases (PTPases) form a novel and important class of cell regulatory proteins. We evaluated the expression of PTPases in mouse ...
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