protein tyrosine phosphatases: characterization of

Protein tyrosine phosphatases: characterization of extracellular and intracellular domains

Robert J Mourey and Jack E Dixon

University of Michigan, Ann Arbor, USA

Protein tyrosine phosphatases (PTPs) play an important role in the regulation of cell growth and differentiation. With over 30 PTPs identified, the specific functions of these enzymes are now being addressed. The identification of extracellular domain receptor-like PTP interactions and the characterization of intracellular PTP ‘targeting’ domains represent recent efforts in this pursuit.

Current Opinion in Genetics and Development 1994, 4:31-39

Introduction

The importance of protein tyrosine phosphorylation in growth, differentiation and cytoskeletal integrity has been well established over the past decade. Protein tyrosine phosphatases (PIPS), enzymes that hydro- lyze phosphotyrosyl groups, were initially considered to play ‘housekeeping’ roles by returning the tyrosine phosphorylation state of target substrates back to basal levels. This overly simplistic view now seems to be incorrect, since a number of PTPs have been shown to regulate integral components of signal transduction pathways (for recent reviews, see 11”,2*,3**1). PTPs have been implicated in tumor suppression 14,5,6’,7-91, cytoskeletal reorganization llO*“,ll*l, development and differentiation 112**,13,14**1, mitotic induction [15g,16,17*l, T-cell activation 118.1, and in growth factor 119’-21*,22-241, somatostatin 1251 and interferon [26”,27*1 signaling pathways. This review will focus on recent advances in understanding the function of receptor-like PTP extracellular domains, as well as the role of specific ‘zip code’ domains that govern intracellular PTP subcellular localization.

Protein tyrosine phosphatase structural domains

PTPs can be separated into two major groups: transmembrane receptor-like PTPs (Fig. 11, and intracellular PTPs (Fig. 2). All PTPs possess at least one catalytic domain of approximately 250 amino acids which contains the ‘active site’ signature motif WV)HCXAGMCRWT)G (in the one-letter amino acid code, where X can be any amino acid) 13”,28”1. Studies using chemical modifl- cation and site-directed mutagenesis have established

that the cysteinyl residue within this consensus motif is essential for phosphatase activity, forming a thio- phosphate enzyme intermediate necessary for catalysis 1291. This catalytic domain is unique to PTPs, bear- ing little resemblance to the catalytic domains of serine/threonine protein phospahatases, alkaline protein phosphatases, or acid protein phosphatases.

The receptor-like PTPs (Fig. 1) possess an extracellular domain, a single transmembrane domain, and usually two intracellular PTP catalytic domains. The first intracellular PTP domain generally accounts for the majority of catalytic activity, while the second domain is inactive or (in some cases) weakly active 130°1. The only transmembrane PTPs containing a single catalytic domain are human (H) PTPB and Drosophila (D) PTPlOD 131-331. Receptor-like PTPs can be further subdivided into five types on the basis of common features found in the extracellular domain [l”l. Type I is represented by the CD45 family, exhibiting multiple isoforms aris- ing from differential splicing of sequences at the amino terminus 1341. Type II members (e.g. LAR, HPTPK, and HPTPl,t) contain tandem repeats of immunoglobulin- like and libronectin type III-like domains resembling neural cell adhesion molecules 135,36,37*1. Type III members bear multiple fibronectin type III-like repeats (e.g. DPTPlO and DPTP99A) [32,33,381. HITPa and HPTP& represent type IV isoforms, possessing small glycosylated segments 131,391. Type V constituents include HPTP< and IWIPy, which exhibit amino-terminal carbonic anhydrase-like domains [40,41’1. Although the structural features of the receptor-like PTPs suggest that they may bind ligands, no ‘ligand’ interaction has yet been identified. However, the extracellular domain of a receptor-like PTP has recently been shown to mediate cell-cell aggregation via homophilic binding [42-,43-l.

Abbreviations CA-carbonic anhydrase; CAM-cellular adhesion molecule; ECF-epidermal growth factor; D-Drosopbib;

CFR-growth factor receptor; H-human; LAR-leukocyte common antigen related molecule; MAP kinase-mitogen-activated protein kinase; PEST-proline-, glutamic acid-, wine- and threonine-rich;

PTK-protein tyrosine kinase; F’TP-protein tyrosine phosphatase; SHZ-Src homology 2; TCR-T-cell receptor.

0 Current Biology Ltd ISSN 0959-437X

32 Oncogenes and cell proliferation

-

LAR DPTPl OD -

Type 1 II III IV V

Q 1994 Currenl Opinion in Genetics and Developmenl

Intracellular PTPs (Fig. 2) possess a single catalytic domain with flanking regions that often contain amino acid sequences which direct the enzyme to specific intracellular locations. These zip code sequences can target PTPs to the endoplasmic reticulum (e.g. PTPlB) 144,45*1, to the nucleus (e.g. DPTPblF) [46..1, or per- haps result in their rapid degradation (e.g. PTP-PEST) [47'1. Several amino-terminal structural motifs have been identified that may direct intracellular PTPs to interact with cytoskeletal proteins (e.g. HPTPMegl, HPTPHl) 148,491 or with phosphotyrosine-containing proteins via Src homology 2 (SH2) domains (e.g. PTPlC, SH-PTP2) [50,51’].

Transmembrane protein tyrosine phosphatases and extracellular domain interactions

CD45 The receptor-like structure of transmembrane PTPs suggests that they may interact with ligands. CD45,

Fig. 1. Transmembrane receptor-like PTPs. The members of this family of PTPs possess a single transmembrane domain, and one or two intracellular PTP catalytic domains (black bar). They can be subdivided into five types on the basis of their extracellular domain structures: I, for example CD45; II, for example LAR and HPTPp; III, for example DPTPl OD and DPTP99A; IV, for example PlPTPa; and V, for example HPTP( and HPTpr [l**]. The extracellular domain structures are shown: amino terminus isoforms (horizontal lines) resulting from differential splicing; immunoglobulin-like (vertical lines); fibronectin type Ill-like (shaded bar); MAM adhesive protein homology-like (diagonal lines); and carbonic anhydrase-like (stippled).

the first transmembrane PTP to be identified 1341, has served as a model for understanding the function of the receptor-like PTPs. CD45 plays a role in T-cell receptor (TCR) mediated signal transduction and has been shown to reconstitute TCR signaling in CD45-deficient T cells [18*,521. In an effort to determine whether the extracellular domain of CD45 influences its function in TCR signal transduction, Desai et al. [53"1 constructed a chimera of the epidermal growth factor (EGF) receptor extracellular domain and the CD45 intracellular domain. The expression of this chimera in CD45-deficient T-cells restored TCR signal transduction (measured as intracellular calcium flux), indicating that the extracellular domain of CD45 is not absolutely required for TCR signaling. When EGF was added, TCR signaling was inhibited. The coexpression of a truncated EGF receptor (missing its cytoplasmic domain) with the EGF receptor/CD45 chimera restored TCR signaling. This suggests that the chimera may dimerite on addition of EGF, resulting in inactivation of intracellular PTP activity. Expression of sufficient truncated EGF receptor would presumably prevent chimera self-as-

Protein twosine DhosDhatases Mourev and Dixon 33

. . . . . . -*..*..I PTPlB . . . . . .

r------ll DPTP61 F

w-1 PTP-PEST

1-B PTPMegl

mh\\\\l-I PTPlC

m VHl

0 1994 Currenl Opinion in Genetics and Development

Fig. 2. Intracellular PTPs. The members of this family of PTPs possess a single catalytic domain (black bar) with flanking regions that often contain intracellular ‘targeting’ domains. Carboxy-terminal domains can target PTPs to the endoplasmic reticulum (stippled) for PTP 16, to the nucleus (shaded box) for DPTP6lF, or result in their rapid degradation (vertical lines) for PTP-PEST. Amino-terminal domains may direct PTPs to interact with cytoskeletal proteins (horizontal lines) for PTPMegl, or with phosphotyrosine via SH2 domains (diagonal lines) for PTPlC.

sociation. Data have also been published suggesting that CD45 is tyrosine-phosphorylated following TCR activation 1541. The specific effects of phosphorylation are unknown. It has been proposed that endogenous ligand-induced dimerization of CD45 may lead to trans- dephosphorylation and functional inactivation, anal- ogous to the dimerization, transphosphorylation and activation of receptor protein tyrosine kinases (PTKs) 1551.

Cell adhesion molecule-like protein tyrosine phosphatases Type II receptor-like Ill’s share extracellular domain similarities to cell adhesion molecules (CAMS). PTI’p and 1vK contain one immunoglobulin-like domain and four libronectin type III repeats 136,371. In addition, they both contain an ‘MAM’ (meprin, A5, cl> motif amino-terminal to the immunoglobulin-like domain. MAM motifs span approximately 170 amino acids and contain four conserved cysteines that may form disulfide bridges [56'1. The function of this domain is unknown. However, the MAM motif occurs in several diverse transmembrane adhesion proteins (e.g. A5 and meprin) and may therefore contribute ‘adhesive’ properties to I’TI’p and ITPK.

The sequence similarity of type II PTI’s to CAMS has led researchers to suggest that these I’TI’s also promote homophilic binding. Expression of full-length I’TI’p in SF9 insect cells results in cell aggregation, suggesting that 1’TIQ.t may mediate this process [42”,43”1. The expression of cytoplasmic domain-deleted constructs indicates that PTP catalytic activity is not required for the observed adhesion; only the extracellular domain is essential for cell-cell interactions. This was further substantiated by the observation that purified extracel-

lular domain conjugated to resin beads can mediate bead-bead adhesion. Work from Schlessinger’s labo- ratory, reported in a ‘research news’ article in Science [57”1, indicates that the closely related molecule M’PK also displays homophilic adhesive properties [57”1. When cells expressing PTPp are mixed with cells expressing PTPK, the cells segregate and adhere in a homophilic fashion. This shows that although PTpp and M’PK are structurally very similar, they display a high degree of specificity in their cell-cell adhesion. In addition, structurally similar L4R is not known to undergo homophilic interactions.

Carbonic anhydrase-like protein tyrosine phosphatases Type V transmembrane PTPs contain a carbonic anhydrase (CA)-like domain in the amino-terminal 300 amino acids of their extracellular domain. These PTIJS include the neural-specific human Ml’< [401, mouse RPTPB i58.1, rat PTI’18 ([59l; RJ Mourey, KL Guan, un- published data), and RFTPy [41*1, which is expressed in kidney, brain and lung. The CA domains of these PTI’s are 25-40% identical to the seven isotypes of CA. It is unlikely that this domain functions as a carbonic anhydrase, since two of the three essential his- tidy1 residues required for catalysis are missing. Rather, the overall structure of the CA domain may be utilized for ligand binding. Indeed, computer modeling of this domain and comparison with the crystal structure of CA indicates that 11 of the 19 residues that form the active site of CA are conserved [41*1. Interestingly, the type V ITS show the same degree of identity to CA as does the vaccinia virus transmembrane protein D8 over almost its entire external domain, lacking two of the three catalytically required histidines [6Ol. Evi- dence suggests that the function of D8 is adsorption of the vaccinia virus to cell surfaces [6ll. The shared homology between Gaccinia D8 and this subclass of PTPs suggests that the D8 binding site may be a potential ligand for these PTI’s.

Targeting of intracellular protein tyrosine phosphatases to specific subcellular locations

SH2 domains The Src homology 2 (SH2) domain is a conserved sequence motif of approximately 100 amino acids that promotes interactions between cytoplasmic signaling molecules and specific phosphotyrosyl residues on activated (i.e. autophosphorylated) growth factor receptors or other signaling molecules. These interactions bring the appropriate signaling components of mito- genie pathways together [62**,6Y,641. Over the past two years, several new PTPs that contain two SH2 domains in their amino-terminal regions have been identified. These include PTI’IC [501 and its homologs (SH-PTPl 1651, HCP 1661 and SHP [bfl), which are expressed predominantly in hematopoietic cells. More ubiquitously expressed SHZcontaining I’Tl’s include

34 Oncoaenes and cell woliferation .

SH-MP2 El*1 and its homologs (Syp &%Pl, PTPlD [69”1, PTPZC [701, and SH-PTP31711).- -

Evidence that these SH2-1’TPs~may play a role in signal transduction comes from the characterization of two developmental genes, Hcph 114**,721 and corkscrew (csw) 173”l. Mice homozygous for the recessive al- lelic mutation motheaten display severe hematopoietic abnormalities [14”,721. These mutations were recently localized to the Hcph gene, which encodes the SHZ-containing 1”Il’ hematopoietic cell protein phosphatase 1661. Abnormalities in this protein may lead to defective signaling in hematopoiesis. Further evidence for the role of SH2-PTI’s in signal transduction is provided by the Drosophila gene csw. This gene encodes an SHZ-Ml’ that functions in the terminal class signal transduction pathway essential for normal development of anterior and posterior segments of the Drosophila embryo 173”l. Genetic experiments suggest that csw interacts with polehole (the Drosophila homolog of c-raf, 1741 to transduce signals generated from the receptor PTK torso (a I’DGF receptor homolog) 1751. The csw protein has high sequence identity with SH-PTP2 and may share functional similarities as well 176’1.

The exact nature of the interaction of SHZcontain- ing IJTI’s with PTKs to positively transduce signals is unclear, although several possible models have been suggested 176’1. One possibility is that the amino-terminal SH2 domain of the PTI’ binds an activated growth factor receptor (GFR), allowing the second SH2 domain to bind other phosphotyrosyl proteins. In this way, the PTI’ is acting to bring proteins to the GFR for further phosphorylation, or to participate in other protein-protein interactions. In an alternative model, SHZ-binding of I’TI’s to GFRs may allow the PTI’ to dephosphorylate nearby phosphotyrosyl-regulated proteins. For example, activation of the insulin receptor results in the association of Syp with tyrosine-phosphorylated insulin receptor substrate 1, a protein participat- ing in the insulin receptor signaling pathway 177’1. In addition, the proximal I’TI’ may dephosphorylate and inactivate GFRs, thus terminating signal transduction. It is important to realize, however, that these two models may not be mutually exclusive

A third mechanism of SHZI’TP-mediated GFR signal transduction has been suggested by more recent results. In this model, the SH2 domains facilitate PTP-GFR interaction, whereupon the PTI’ is subse- quently tyrosine-phosphorylated. The phosphorylated MI’ could then interact with other SHZ-containing proteins in signal transduction. In addition, tyrosine phosphorylation may increase 1’TI’ catalytic activity, potentially increasing the dephosphorylation of downstream effector molecules. Both Syp and PTI’lD were shown to associate in vivo with activated I’DGF and EGF receptors [68*,69..1. Both 1’TI’s failed to dephosphorylate the GFR, .but were themselves tyrosine-phosphorylated. I’hosphorylation of SH2-PTI’s may be required for interaction with receptor tyrosine kinases and other signaling molecules 168’,69”,76’,78’1. In the case of

PTPID, phosphorylation is correlated with a small increase in I’TI’ catalytic activity in vitro [69”1. These findings indicate that SH2-FTPs may interact with PTKs, not simply to inactivate the GFR, but rather to work in concert with the GFR to regulate the phosphorylation state of signal transduction effector molecules.

Nuclear-targeting domains Recently, several I’TPs were shown to localize to the nucleus [46”,79’1, which is intriguing given the suggested functional role of I’TI’s in cell cycle regulation and gene transcription [15*,16,26”,27*1. In the case of the Drosophila I’TI’ Dl’TI’61F, alternative splicing can produce two different carboxy-terminal zip codes directing the PTI’ to alternative locations 179’1. Expression of each alternatively spliced form in COS-1 cells indicated that the form possessing a highly ba- sic 11 amino acid carboxyl terminus was directed to the nucleus. The other Dl’TI’61F species, containing a carboxy-terminal splice of 24 hydrophobic amino acids, was localized to a ‘reticular’ network and mitochondria-like organelles within the cell. The substrate specificities of the nuclear and membrane 1’TI’s were indistinguishable, as expected, since they share the identical catalytic domain. This underlines the fact that subcellular location can define and restrict the substrate specificity of PTI’ases within the cell.

Endoplasmic reticulum-targeting domains 1’TI’lB was originally purified from placental tissue as a soluble 39 kDa protein [Sol. However, the molecular cloning of rat and human I’TI’lB predicted a SO kDa protein containing a hydrophobic carboxyl terminus 181,821. Frangioni et al. 1441 and Woodford-Thomas and co-workers 145.1 showed that full length PTI’lB is nor- mally localized to the endoplasmic reticulum in cells and that this localization is dictated by the carboxy-terminal 35 amino acids. Expression of carboxy-terminal truncated I’TI’lB results in a soluble enzyme. I’TI’lB can be released from the endoplasmic reticulum partic- ulate fraction by trypsinitation. The targeting of PTI’s to the endoplasmic reticulum via their hydrophobic car- boxy1 terminus may result in limited substrate availabil- ity and act to keep PTI’s in reserve until a cellular stim- ulus induces translocation of the PTI’ to the cytoplasm by carboxy-terminal proteolysis. Such an agonist-mediated stimulation of proteolysis and subsequent release of soluble PTI’ is observed in platelets [83’]. Activation of platelets by mixing, thrombin, or antibody engage- ment of the fibrinogen receptor gpIIb-IIIa, results in the activation of calpain, a calcium-dependent neu- tral protease. Activated calpain then cleaves I’TI’lB between its catalytic domain and its membrane-anchor- ing carboxyl terminus, resulting in a soluble I’TI’. The cleavage of PTI’lB correlates with irreversible platelet aggregation 183’1. In addition, cleavage and subcellular relocation of PTI’lB results in a twofold stimulation of its enzymatic activity and an altered pattern of phosphotyrosyl-substrate dephosphorylation [83*].

Protein tvrosine phosphatases Mourev and Dixon 35

Dual specificity tyrosine/serine protein phosphatases

The first member of the class of dual specificity PTPs was identified in vaccinia virus 1841. This phosphatase, VHl, is a small (20 kDa) soluble phosphatase (Fig. 2) that dephosphorylates both phosphotyrosine- and phosphoserine-containing substrates. VHl-like phosphatases have also been identified in smallpox variola virus, several orthopoxviruses and baculovirus 1851. In mammals, several VHl-like phosphatases have been cloned and shown to be induced as immediate-early genes. The synthesis of human T-cell PAC-1 179’1, human CL100 1861 and the mouse homolog 3CH134 120’1 is induced by serum growth factors and oxidative or heat stress. In addition, a yeast VI-D-like phosphatase has been shown to be induced upon nitrogen starvation 1871.

Serum growth factors activate transmembrane protein tyrosine kinases 1881. Mitogen-activated protein kinase (MAP kinase) has been shown to be a major component of the signaling pathway involved in transducing the signal from activated I’TKs to downstream effector molecules 1891. MAP kinase (~42) is activated by phosphorylation on Thr183 and Tyr185 by MAP kinase kinase 1901. The dual specificity phosphatases appear to dephosphorylate activated MAP kinase. Transcrip- tion of 3CH134 VFD-like phosphatase is rapidly induced by mitogenic stimulation, and synthesis occurs within the first hour 120’1. 3CH134 dephosphorylates Thr183 and Tyr185 on activated MAP kinase both in vitro and in vivo 191**1. In serum-stimulated iibrob- lasts, the inactivation of MAI’ kinase coincides with the new synthesis of 3CH134 [91**1. Expression of 3CH134 in COS cells blocks serum-stimulation of MAP kinase, while the expression of a catalytically inactive 3CH134 augments MAP kinase phosphorylation. In addition, inactive 3CH134 can be immunoprecipitated with phosphorylated MAP kinase demonstrating a physical interaction 191**1. These findings suggest that 3CH134 may be the physiological MAP kinase phosphate.

Conclusions

With the recent characterization of receptor-like I’TP homophilic interactions, investigators can begin to ap- proach the problem of understanding how these cata- lysts regulate signal processing during cell-cell contact. In addition, the characterization of intracellular I’TP targeting domains will allow researchers to begin to determine how the substrate specificity of these enzymes is controlled. Characterization of targeting domains will also provide clues about PTP localization and function in the cellular landscape.

Acknowledgements

We wish to thank our colleagues Randy Stone and Zhong-Yii Zhang for their helpful comments in review of this manuscript. This work was supported in part by grants from the National In- stitutes of Health and the Walther Cancer Institute. Robert J Mourey is a Bristol-Myers Squibb Pharmaceutical Re.search Institute Fellow of the Lie Sciences Research Foundation.

References and recommended reading

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32. YANG X. SEOW KT. BAHRI SM, OON SH, CHIA W: ‘Iwo Druso@Ua Receptor-Like Tyrosinc Phosphatase Genes Arc Expressed in a Subset of Developing Axons and Pioneer Neurons in the Embryonic CNS. Cell 1991, 67:661673.

33. TIAN SS, Tsoulsti P, ZINN K: Three Receptor-Linked Pro tein Phosphatascs arc Selectively Expressed on Central Ncr-

Protein tyrosine phosphatases Mourey and Dixon

34

36.

37. .

vous System Axons in the Drosopblka Embryo. Cell 1991, 67:675-685.

CHARDONNWU H, TONKS NK, WA&H KA, FISCHER EH: The Leukocyte Common Antigen (CD45): a Putative Rcccptor- Linked Protein Tyrosinc Phosphatasc. Pra- Nut1 Acad Scf USA 1988, 85:7182-7186.

SIREULI M, KRUEGER NK, HALL LR, SCHLOSSMAN SF, Sluro H: A New Mcmbcr of the hnmunoglobuiin Sup&amity that has a Cytoplasmic Region Homologous to the Leukocyte Common Antigen. / Exp Med 1988, H&:152%1530.

GERBINK MF, VAN EI-IXN I, HXIXBO~R G, SUIJKERBUIJK R, BEIJERSBERCEN RL, Geutt’is VAN KESXL A, MOOLENMH WH: Cloning, Expression and Chromosomai Localization of a New Putative Receptor-Like Protein Tyrosinc Phosphatasc. f+iEs .Lett 1991, 290:123-V%).

JIANG YP, WANG H, D’ELJSI’ACHIU P, MUSACCHIO JM, SCHLE~~INGER J, SAP J: Cloning and Characterization of R- PIP-K, a New Mcmbcr of the Receptor Protein Tyrosinc Phosphatasc Family with a Protcolyticaily Clcavcd Cellular Adhesion Molecule-Like ExtraccUuiar Region. Mel Cell Efol 1993, 13:2942-2951.

Describes the cloning of a receptor-like PTP that defines the PTP subclass having homology to cell adhesion molecules. Members of this subclass are post-transiationally modified by proteolytic cieav- age of their extracellular domain and may piay a role in ceU*eU recognition, adhesion and development.

38.

39.

40.

41. .

HARIHARAN IK, CHUANG PT, HUUIN GM: Cloning and Charac- terization of a ReceptorClass Phosphotyrosinc Phosphatasc Gcnc Exprcsscd on Ccntmi Nervous System Axons in Lhsopblla melanogaster. Proc Nat1 Acud Sci USA 1991, 88:11266-11270.

KREUGEH NK, SIHEULI M. SAITO H: Structural Diversity and Evolution of Human Receptor-Like Protein Tyrosinc Phos- phatascs. bM190 J 1990, 9:3241-3252.

KRUEGER NX, SAII’O H: A Human Transmcmbranc Protcin- Tyrosinc-Phosphatasc, PTP<, is Exprcsscd in Brain and has an N-Terminal Receptor Domain Homologous to Carbonic Anhydrascs. Proc Natl Acud Scf USA 1992, 897417-7421.

BARNEA G, SILVENNOINEN 0. SHMNAN 8, HONEGGER AM, CANOLL PD, D’EUSI’ACHIO P, Moas~ 8, LEVY JU, LAI;ORCIA S. HUEI~NER K I:/’ AL.: Idcntihcation of a Carbonic Anhydrasc- Like Domain in the Extracciluiar Region of Riley Dctincs a New Subfamily of Receptor Tyrosinc Phosphatascs. Mel Cell B/o/ 1993, 13:1497-1506.

This paper reports the cloning of a receptor-like PTP containing an extmcelluiar domain with homology to carbonic anhydrdse. Together with the identification of HPTP< I401, these PTPs define a new subfamily of receptor-like PTPs. In addition, computer modeling indicates the carbonic anhydrdse domain structure is retained in this PTP, although .scverdi residues required for cataiysis are missing, suggesting another Function for this domain.

42. BRADY-KALNAY SM. FLINI’ AJ, TONKS NK: HomophiUc Binding . . of PTPit, a Receptor-Type Protein Tyrosinc Phosphatasc, Can

IMediate Cell-Cell Aggregation. J Cell Bfvll993, 122961-972. A rigorous piece of work identifying the first ‘ligand’ for receptor- like PTPs. This paper demonstrdtes the ability of PTPp to mediate cell-cell homophilic adhesion independently of its PTP clltalytic activity.

43. GEBBINK MFDG, ZONDAG GCM. WlJIII~Ol.‘l’S HW, . . BEIJERSB~RG~N RL. VAN EI-IXN I, M~XX~NAAH WH: Cell-Ccli

Adhesion IMediated by a Receptor-Like Protein Tyrosinc Phosphatasc. J Efol Cbem 1993, 268:16101-16104.

An excellent communication reporting the identification of PTPu as its own Ugand. fzdcilitating homophilic cell-cell adhesion.

44. FRANGIONI JV, BEAH# PH, SHIFHIN V, Josr CA, NEEI. BG: The Nontransmcmbranc Tyrosinc Phosphatasc PTF-1B Localizes to the Endoplasmic Reticulum via Its 35 Amino Acid C- Terminal Sequence. Cell 1992. 68:545-560.

45. MAUI~O LJ, WOODPORD-THOMAS TA, POT DA, TAPA~~OW~KY . EJ, DIXON JE: Targeting of an 1ntraccUular ‘lyrosmc Phos

phatasc: Mechanisms and Functional Rclcvancc. Adv Ptut Pbospbatases 1993, E393-411.

A thorough review describing the role of the C-terminal extension in targeting PTPl to the endopiasmic reticulum and its functional sig- nificance.

46. M~UGHUN S, DIXON JE: Alternative Splicing Gives Rise to . . a Nuclear Protein Tyrosinc Phosphatasc in Dnxopbfka. J

Biol Cbem 1993, 2686839-6842. A novel finding demonstrating that intmceUular targeting of PTPs can be dictated by alternative splicing, which may add carboxy-terminal extensions directing PTPs to cytopkrsmic membrdnes or the nucleus. 47. YANG Q, Co D, S~MMERCORN J, TONKS NK: Cloning and

Expression of Fq’PPEST. J Bfol Cbem 1993, 268:6622&% ke cloning of a novel PTP containiig a carboxy-terminal PEST sc- quence that potentially determines a shon intracelluiar half-life. 48.

49.

50.

51. .

Gu MX, YORK JD, WARSHAWSKY I, MAJERUS PW: Idcntifica- tion. Cloning, and Expression of a Cytosolic Mcgakaryocytc Protein-Tyrosinc-Phosphatasc with Scqucncc Homology to Cytoskclctai Protein 4.1. JVoc Nat1 Aud Scf USA 1991, 885867-5871. YANG Q, TONK~ NK: Isolation of a cDNA clone Encoding a Human Protein-Tyrosinc Phosphatasc with Homology to the Cytoskcictal-Associated Proteins Band 4.1. Ezrin, and Talin. Prvc Natl Acad Scl USA 1991, 88:5949-5953. ZHAO Z, DOUCHARD P, DIL-~~ CD, SHEN SH, FISCHER EH: Purification and Characterization of a Protein Tyrosinc Phosphatasc Containing SH2 Domains. J Bfol Cbem 1993, 2682816-2820. FREEMAN JRM, PLUIZKY J, NEEL BJ: Identification of a Human Src Homology 2Containing Protein-Tyrosinc-Phosphatasc: a Putativc Homolog of Lkxopblla Corkscrew. PIWC Nat1 Acad .%l USA 1992, 8911239-11243.

The identification and cloning of an SHZ-containing PTP that may be the mammalian homolog of corkscrew, a member of the torso receptor tyrosine kinase signal trdnsduction pathway in Dmvopbffa.

52. RANKIN BM, YOCUM SA, MIITLER RS, KIENER PA: Stimulation of Tyrosinc Phosphorylation and Calcium Mobilization by FC-T Receptor CrossLinking: Regulation by the Phosphoty- rosinc Phosphatasc CD45. J Immrrnol 1993, 150605616.

53. DFSAI DM, SAP J, SCHLESSINGER J, WEISS A: L&and-Mediated . . Negative Regulation of a Chimcric Transmembranc Receptor

Tyrosinc Phosphatasc. Cell 1993, 73541-554. A classic paper demonstrdting that ligand binding may facilitate dimerixation of a receptor-like PTP, thereby negatively regulating its activity. The data suggest the novel idea that l&and-mediited rcguiation of receptor-PTPs may have mechanbXic similarities with receptor tyrosine kinases. 54. SI‘OVER DR. CHARRONNFAU H. TONKS NK, WALSH KA: Protein-

Tyrosinc-Phosphatasc CD45 Is Phosphorylatcd Transiently on ‘Iyrosinc Upon Activation of Jurkat T Cells. Pnx: Nat1 Acad Scf USA 1991, 88~7704-7707.

55. LAMMEHS H, VAN OI~BERGHEN E, DAI.LOIV R, .SCHLR%SINGER J, ULLRICH A: Transphosphorylation as a Possible Mcch- anism for Insulin and Epidcrmal Growth Factor Receptor Activation. J Efol Chem 1990, 265:16886X%0.

56. BECKMANN G, BARK P: An Adhcsivc Domain Detected in . Functionally Divcrsc Receptors. Trend Biocbem Sc’f 1993,

lB:4+41. A report of a consensus motif that is associated with several adhesive proteins.

57. EIJGENRAAM F: Things Start Getting Sticky for a CcU Surface . . Enzyme. Scfence 1993, 261:833. A ‘research news’ article describing results from severdi labordtories that PTPp and FTPK mediate cell-cell adhesion through homophilic interdctions.

58. LEW JB, CANOLL PD, SILVENNOINEN 0, BAHNFA G, Mot% B, . HONECCER AM. HIJANC IT. CANNIZZARO LA. PARK SH. DRUCK

37

38 Oncomws and cell woliferation .

T, m AL.: The Cloning of a Rcccptopllpc- Protein Tyrosinc Phosphatasc Expressed in the Central nervous System. / Biol Cbem 1993, 268:10573-10581.

This paper describes the identification of a carbonic anhydrase- like domain in a brain-specific trdnsmembnne FTP. This PTP is developmentally-expressed and may therefore play a role in central nqrvous system development.

59. GIJAN K-L, DIXON JE: Protein Tyrosinc Phosphatasc Activity of an Essentij Virulence Determinant in Yersfnla. Science 1990. 249~553556.

60. NILES EC, SLT~ J: vaccinia Virus Gene DS Encodes a Virion Transmembranc Protein. / Vim/ 1988, 62:3772-37/S.

61. MM J-S, RODRIQUI-X JF, ESI’EIIAN M: Structural and Functional Characterization of a Cell Surface Binding Protein of vaccinia Vi. J Btol Cbem 1990, 26531569-1577.

62. FANS. WJ, JOHNSON DE, WII.I.IAMS LT: Signaling by Receptor . . Tyrosinc Kinascs. A’nntr Reu Biocbem 1993, 62:453-481. An wcellent review of recent biochemical and cellular studies detailing signal transduction by receptor tyrosine kinases and their signaling pathway components. A thorough description of the receptor tyrosine kiise subfamilies is discussed.

63. SCHLF~INGER J, MOHAMMAIX M, MARGOLIS B, ULLRICH A: Role . of SHZContaining Proteins in Cellular Signaling by Receptor

Tyrosine Kinases. COW Spring Hurb $vrnp Quant Bioll992, 57~67-74.

This paper presents models of how SHZ-containing proteins participate in receptor tyrosine kin&se signaling pathways. A current list of SHZ-containing proteins and their functions is discussed.

64. FELDER S, 2~0~ M, HU P, URF~A J, UI.I.RICH A, CHAUUHUR M, WHITE M, SHOEISON SE, SCHLF~~INGER J: SH2 Domains Ex- hibit High-Affinity Binding to TyrosincPhosphorylatcd Prp tides Yet Also Exhibit Rapid Dissociation and Exchange. Mel Cell Biol 1993, 13:1449-1455.

65. PEI D, NEEL BG, WALSH CT: Overocprcssion, Puriication, and Characterization of SHPTPl, a Src Homology 2-Contain- ing Protein-TyrosincPhosphatase. Proc Nat1 Acad St3 USA 1993, 90:1092-1096.

66. YI T, CLEVELAND JL, IHLE JN: Protein Tyrosinc Phosphatasc Containing SH2 Domains: Characterization. Preferential Ex- pression in Hematopoictic Cells, and Localization to Human Chromosome 12p12-~13. Mot Cell Blol 1992. 12:836-846.

67. SHEN SH, BA.TIIEN L, POSNER BI, CHWIWN P: A Protcin-Ty- rosinc Phosphatasc with Sequence Similarity to the SH2 Domain of the Protein-Tyrosinc Kinascs. Nature 1991, 352:736-739.

68. FENG G, HUI C, PAWX)N T: SHZContaining Phosphotyrosinc . Phosphatasc as a Target of Protein-Tyrosinc Kinascs. Science

1993, 259~1607-1611. This paper repons the identification of the SHZ-containing PTP, Syp, and describes its in tioo association with activated epidermal and platelet-derived growth factor receptors. The function of Syp in mammalian embryonic development and its role as a target for both receptor and non-receptor tyrosine kinases is discussed.

69. VOGEL W, LAMMERS R, HUANG J, ULLRICH A: Activation of a . . Phosphotyrosinc Phosphatasc by Tyrosinc Phosphorylation.

Science 1993. 2591611-1614. Describes the identification of an SHZ-containing PTP, PTPlD, and shows its fn vfm) association and phosphorylation (as in [68*1). The PTP identified in I6801 is a C-terminal splice variant of PTPlD. The novel finding, that the physical interaction of a PTP with a protein tyrosine kinase results in PTPase activity modulation, is presented.

70. AHMAD S, BANVILLE D, ZHAO 2, FLXHER EH, SHEN S-H: A Widely Expressed Human Protein-Tyrosinc Phosphatasc Con- taining Sn: Homology 2 Domains. Proc NutI Acad Sci USA 1993, 90:2197-2201.

71. ADACHI M, SEKIYA M, MIYACHI T, MA’IXJNO K, HINODA Y, IMAI K, YACHI A: Molecular Cloning of a Novel Protcin-

72.

73. . .

74.

75.

76. .

Tyrosinc Phosphatasc SH-F’TP3 with Sequence Similarity to the &-Homology Region 2. FEES L&t 1992, 314335339.

TSUI HW, SIMINOVIICH KA. DE SOUSA I, TSUI FWLZ mot&e aten and uiu&ie Mice have Mutations in the Hacmatopoictic Cell Phosphatasc Gene. Nuture Gznet 1993, 4:124-129.

PERKINS LA, LARSEN 1. PERIUMON N: conhscmru Encodes a Pu- tativc Protein Tyrosinc Phosphatasc that Functions to Trans duct the Terminal Signal from the Receptor mosinc Kinasc torso. Cell 1992, 70:225-236.

AMUROSIO L, MAHOWALD A, PERRIMON N: Requirement of the Lhsopblka raf Homologue for torso Function. Nature 1989, 342:288-290.

SPRENGER F, SIEVENS LM. NUSSLEIN-VOLHARD C: The Lhvsopbffa Gene torso Encodes a Putative Receptor Ty- rosinc Kinasc. Nature 1989, 338~478-483.

LECHLEIDER RJ, FREEMAN RM JR, NEEI. BG: Tyrosyl Phosphory- lation and Growth Factor Receptor Association of the Hu- man corkscrew Homologue, SH-PTP2. J Bfol Cbem 1993, 268:13434-13438.

This paper provides evidence for the association and subsequent tyrosine phosphorylation of SH-PTP2 with activated growth factor receptors. Seveml models of SH-PTP signaling are presented.

77. KUHNE MR, PAWSON T, LIENHARD GE, FENG G-S: The In- . sulin Receptor Substrate 1 Associates with the SHZContain-

ing Phosphotyrosinc Phosphatasc Syp. J Bfol Chem 1993, 268:11479-11481.

A report describing the association of an SHZ-containing PTP with an insulin receptor pathway signalin component. These findings suggest that tyrosine phosphorylated-IRS-1 may act as a docking protein for SHZcontaining proteins, recruiting these proteins for insulin signaling.

78. YEUNG YG, BERG KL. PIMXY FJ, &GEI.FI-II RH, STANLEY ER: . Protein Tyrosinc Posphatasc-lc Is Rapidly Phosphorylatcd in

Tyrosinc in Wacrophagcs in Response to Colony Stimulating Factor-l. J Bfol Chem 1992. 267:23447-23450.

This communication describes the rapid, growth factor-induced tyrosine phosphorylation of the intracellular phosphatase, PTP-1C. impli- cating its role in an early event in growth factor signal tmnsduction.

79. ROHAN PJ, DAVIS P, MOSKALUK CA, KEARNS M, KRIrI-ZSCH H, . SIEDENLISI’ U. KELLY K: PAC-1: a Mitogcn-Induced Nuclear

Protein Tyrosinc Phosphatasc. Science 1993, 259:17631766. Describes the cloning of a nuclear-localized PTP which possesses dual specificity for phosphotyrosyl- and phosphoseryl-containing substrates.

80. TONKS NK, DIL’IZ CD, FISCHER EH: Purification of the Ma- jor Protein-Tyrosinc-Phosphatases of Human Placenta. J Biol Cbem 1988, 263:6722-6730.

81. GUAN KL, HAUN RS, WA‘ISON SJ, GEAHLEN RL, DIXON JE: Cloning and Expression of a Protein-TyrosincPhosphatasc. Proc Nat1 Acad Sci USA 1990, 87:1501-1505.

82. Chernoff J, Schievella AR, Jost CA, Erikson RL, Neel BG: Cloning of a cDNA for a IMajor Human Protcin-Tyrosine- Phosphatasc. Proc Nat1 Aud Sci USA 1990, 87:2735-2739.

83. FRANGIONI JV, 01,~ A. SMI’I’H M. SALZMAN EW, NEEL BG: . CalpainCatalyzed Cleavage and Sulxcllular Relocation of

Protein Phosphotyrosine Phosphatasc 1B (PlT-IB) in Hu- man Platelets. &f&30 J 1993, 12:4843-4856.

This paper describes the agonist-mediated stimulation of PTPlB proteolytic cleavage by calpain, resulting in the relocation of FTPlB to the cytosol, a small increase in catalytic activity, and an.alteration in the pattern of tyrosyl phosphorylation.

84. GUAN K, BROYLFS SS, DIXON JE: A Tyr/Scr Protein Phosphatasc Encoded by Vaccinia Virus. Naftrre 1991, 350:353-362.

85. Hl~t~s DJ, MACIBLI. KJ, ZHAO W-G. MASSUNG RF, ESPOSI~I’O JJ, DIXON JE: A Protein Phosphatasc Related to the Vac- cinia Virus VHl is Encoded in the Gcnomcs of Several Or-

Protein tyrosine phosphatases Mourey and Dixon 39

86.

87.

88.

89.

90.

thopoxviruses and a Bacufovirus. Proc Nat1 Acud Sc‘f USA 1993, 904017-4021. ALESSI DR. SMVIHE C. KEYSE SM: The Human CL100 Gene Encodes a Tyr/rhr-Protein Phosphatase which Potently and Specificially Inactivates MAP Kinasc and Suppresses its Ac- tivation by Oncogcnic Ras in Xenopus Oocyte Extracts. Oncogene 1993. 8:2015-2020. GUAN K. HAKES DJ, WANG Y, PAHK H-D, CARPER TG, DIXON JE: A Yeast Protein Phosphatase Related to the Vaccinia VHl Phosphatase is Induced by Nitrogen Starvation. Proc Nat1 Acad Scf USA 1992, 8912175-12179. ULLHICH A, S~HI.F~ING!ZK J: Signal Transduction by Receptors with Tyrosinc Kinase Activity. Cell 1990, 61:20>212. Corm MH, BOULTON TG, ROBBINS DJ: Extracellular Signal- Regulated Kinases: ERKs in Progress. CeN f?q 1991, 2:965-978. PAYNE DM, ROSSOMANIX, AJ, MAR’IINO 1: EHIKSON AK, HER J-H, SHABANOWIIZ J. HUN-I’ DF, WEIXR MJ. S’IURGILL

TW: Identification of the Regulatory Phosphorylation Sites in pp42/Mitogcn-Activated Protein Kinase (MAP Kinase). EMBO J 1991, 10885-892.

91. . .

SUN H, CHARLES CH, LAU L, TONK~ NK: MKP-1 (3CH134). an

A report describing the In ulfro and tn ylvo dephosphotylation of

Immediate Early Gene Product, is a Dual Spccilicity Phos-

MAP kinase by the growth factor induced dual specificity phos-

phatase that Dephosphorylatcs MAP Kinase In VZno. Cell 1993, 75:487493.

phatase, 3CH134. The authors propose that 3CH134 is the physiological MAP kinase phosphatase.

RJ Mourey and JE Dixon, Department of Biological Chemistry, Medi- cal School, Walther Cancer Institute, Medical Science 1, University of Michigan, 1301 E. Catherine Street, Ann Arbor, Michigan 48109-0606, USA.

protein tyrosine phosphatases: characterization of

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