Intracellular tyrosine phosphatases and kinases in lymphoma


Payam Delfani1, Anette Gjörloff Wingren2

1Department of Immunotechnology, Lund University, Lund, Sweden
2Department of Biomedical Sciences, Health and Society, Malmö University, Sweden


March 2012


Tyrosine phosphorylation and dephosphorylation

Tyrosine phosphorylation is a key mechanism for signal transduction and for the regulation of many cellular processes (Mustelin et al., 2005; Tonks, 2006). The protein tyrosine kinases (PTKs) phosphorylate at tyrosine residues and the protein tyrosine phosphatases (PTPs) dephosphorylate. The human PTP genes are divided into several families: Class I cysteine-based PTPs, class II cysteine-based PTPs, class III cysteine-based PTPs and Asp-based PTPs (Andersen et al., 2004; Mustelin et al., 2005). The class I cysteine-based family constitute the largest family of PTPs, and is further classified into 38 classical PTPs and 61 VH1-like "dual-specific" protein phosphatases (DSPs) (Alonso et al., 2004). Of the 38 classical PTPS, 17 are non-receptor intracellular PTPs and 21 are receptor-like transmembrane PTPs. All the classical PTPs are strictly tyrosine-specific (pTyr). In contrast, the VH1-like DSPs are much more diverse and are divided into several subgroups: PTPs specific for mitogen-activated protein (MAP)-kinases (MKPs), atypical DSPs including VHR, VHY, VHX and VHZ, slingshots, PRLs, CDC14s, PTENs and myotubularins (Alonso et al., 2004).
PTPs have a catalytic domain with an intrinsic substrate preference, and most have non-catalytic amino- or carboxy terminal extensions domains that interact with other molecules or targets (Mustelin et al., 2005). The non-catalytic regions can also participate in regulation of phosphatase activity by intramolecular folding mechanisms (Mustelin et al., 2005). It has been long appreciated that PTPs have capacity to function as inhibitors by phosphotyrosine (pTyr)-dependent signaling, but also to act as positive regulators in promoting signaling (Mustelin et al., 1999; Gjörloff Wingren et al., 2000; Andersen et al., 2004; Mustelin et al., 2005; Tonks, 2006). Lymphocytes express 50-60 of the total 107 PTP genes. The most well-studied PTPs in lymphocytes are presented in Table 1 (12 non-receptor intracellular PTPs, PTEN and the class II cysteine-based PTP LMW-PTP).

Table 1. Commonly studied PTP genes in the human genome.

Chromosome location
PTPN1 PTP1B 20q13.1-13.2 Brown-Shimer et al., 1992; Forsell et al., 2000
PTPN2 TCPTP 18p11.3-11.2 Sakaguchi et al., 1992
PTPN3 PTPH1 9q31 Itoh et al., 1993
PTPN4 PTP-MEG1 2q14.2 Gu et al., 1991
PTPN5 STEP 11p15.1 Lombroso et al., 1991
PTPN6 SHP1 (PTP1C, SH-PTP1, HCP) 12p12-13 Plutzky et al., 1992
PTPN7 HePTP (LCPTP) 1q32.1 Zanke et al., 1992; Zanke et al., 1994; Adachi et al., 1994
PTPN9 PTP-MEG2 15q23 Gu et al., 1991
PTPN11 SHP2 (SH-PTP2, Syp, PTP1D, PTP2C, SH-PTP3) 12q24.1 Dechert et al., 1995; Isobe et al., 1994
PTPN12 PTP-PEST 7q11.23 Takekawa et al., 1992; Charest et al., 1995
PTPN13 PTP-BAS 4q21.3 Inazawa et al., 1996; Maagdenberg et al., 1996
PTPN22 LYP (PEP) 1p13.3-p13.1 Cohen et al., 1999
PTEN PTEN (MMAC1, TEP1) 10q23.3 Li et al., 1997; Steck et al., 1997
ACP1 LMPTP (low Mr PTP, LMWPTP, BHPTP) 2p25 Hopkinson et al., 1963


Lymphoma and leukemia

Tumors of the immune system are classified as either leukemia or lymphoma. Leukemias often proliferate as single cells in the blood or lymph while lymphomas tend to proliferate as solid tumors within lymphoid tissues. Historically, the lymphomas have been classified as either Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL), the latter diagnosis being the most common and comprising many different subtypes originating from B-cells, T-cells or natural killer (NK) cells. About 85 % of the NHLs are of B-cell origin and these B-cell lymphomas can be divided into around 15 types according to the World Health Organization (WHO) lymphoma classification (Jaffe et al., 2001; Swerdlow et al., 2008). The various subtypes can have very different clinical behaviours and requirements for treatment strategies, due to the differentiation stage of the B-cell they originated from. As the different stages of B-cell development and maturation are characterized by the structure of the BCR and of the expression of certain differentiation markers, and since the malignant B-cell is said to be "frozen" at the particular stage it developed from, this can be used to determine the cellular origin of the B-cell lymphoma. Diffuse large B-cell lymphoma (DLBCL) is together with B-cell chronic lymphocytic leukemia (CLL), mantle cell lymphoma and follicular lymphoma the most common B-cell lymphomas in adults. DLBCLs exhibit marked biological heterogeneity and variable clinical presentation and clinical course. DLBCL and Burkitt lymphoma (BL) account for the majority of aggressive lymphomas in adults and children. Conversely, BL is genetically relatively homogeneous but associated with variable clinicopathological features (de Leval and Hasserjian, 2009). Gene expression profiling is a powerful tool to uncover complex molecular networks in cancer and, specifically, in malignant lymphomas. Within DLBCL, germinal center B-cell-like (GCB) DLBCL, strongly resembles normal germinal center B-cells and has a good prognosis following chemotherapy, whereas activated B-cell-like (ABC) DLBCL resembles mitogenically activated blood B cells and has a poor outcome (Shipp et al., 2002; Rosenwald et al., 2002). Gene expression profiling furthermore allows the molecular separation of BL from DLBCL and reveals a Burkitt-specific signature which is also expressed by a subset of tumors that are currently classified as DLBCL.

B-cells are especially vulnerable for transforming events during the rearrangements of their BCR, hence the over representation of B-cell lymphomas derived from the GC compartment where somatic hypermutation takes place. Many B-cell leukemias and lymphomas involve an oncogene (mutated and proliferation-enhancing version of a normal gene) that has developed from the corresponding proto-oncogene (normal version of the oncogene) translocated into the Ig-genes. As a consequence, the oncogene is controlled by the Ig-locus and this result in a deregulated, constantly expressed oncogene, contributing to the lymphoma pathogenesis.


Protein tyrosine kinases

PTKs of the SRC (from "neoplastic transformation of cell by avian sarcoma virus is mediated by a single viral gene (src)", one of the most extensively studied retroviral oncogenes), SYK (Spleen tyrosine kinase), TEC (Tec protein tyrosine kinase) and CSK (c-terminal src tyrosine kinase) families are crucial for antigen-receptor induced lymphocyte activation (Ku et al., 1994; Sato et al., 1994; Coussens et al., 1985). LCK (lymphocyte-specific protein tyrosine kinase) (Marth et al., 1985), and the proto-oncogene protein tyrosine kinases FYN (FYN binding protein, FYB-120/130) (Alland et al., 1994; Resh, 1998) and YES (Semba et al., 1985) are expressed in T cells, and LYN (tyrosine protein kinase Lyn) (Yamanashi et al., 1987), FYN and BLK (B lymphocyte kinase) (Dymecki et al., 1990) in B cells. The most well-studied PTKs in lymphocytes are presented in Table 2.

Table 2. Commonly studied PTK genes in the human genome.

Chromosome location
CSK family
CSK CYL 15q23-q24 Sondhi et al., 1998
SRC-A family
FGR SRC2 1p36.2-p36.1 Abram et al., 2000; Schwartzberg, 1998; Thomas and Brugge, 1997
SRC   20q12-q13
YES1   18p11.31-p11.21
SRC-B family
BLK   8p23-p22 Dymecki et al., 1990; Ziegler et al., 1987; Marth et al., 1986; Yamanashi et al., 1987
HCK JTK9, HCTK 20q11-q12
LCK   1p35-p34.3
LYN   8q13
TEC family
BMX ETK, PSCTK2 Xp22.2 Schaeffer et al., 2000; Rawlings and Witte, 1995
BTK ATK, PSCTK1, AGMX1, IMD1 Xq21.33-q22
ITK EMT, PSCTK2 5q31-q32
SYK family
SYK   9q22 Turner et al., 2000; Chu et al., 1998
ZAP70 SRK, STD 2q12

In haematopoietic cells, SRC kinases such as LCK, FYN and LYN are the first protein tyrosine kinases that are activated after stimulation through the immunoreceptors. They phosphorylate ITAMs (immunoreceptor tyrosine-based activation motifs) that are present in the signal transducing subunits of the immunoreceptors, thereby providing binding sites for SRC homology 2 (SH2)-domain containing molecules, such as SYK (Mustelin et al., 2005). The SYK-family kinases, SYK and ZAP70 (ζ-chain-associated protein kinase of 70 kDa) function downstream of the SRC-family kinases to amplify the signal and are focal points for the assembly of signalling complexes (Chan et al., 1991; Bradshaw, 2010; Wang et al., 2010). Many PTKs, such as the SRC-family and SYK-family PTKs found in B and T cells, are tightly controlled by PTPs.

ZAP70 plays a critical role in the events involved in initiating T cell responses by the antigen receptor (Wang et al., 2010). The importance of functional ZAP70 has been revealed by observations of both Zap70 deficient humans and mice. ZAP70 deficient patients have no functional T cells in their peripheral blood and suffer from severe combined immunodeficiency (SCID) (Wang et al., 2010). Apart from the critical role in T cells, ZAP70 is also expressed in some populations of activated B cells and in B cell CLL (B-CLL) (Chen et al., 2007; Gobessi et al., 2007; Chen et al., 2008). B-CLL causes accumulation of monoclonal CD5+ B cells in the blood, bone marrow, lymph nodes and spleen. Several different prognostic factors have been proposed for patients with B-CLL. In around 50% of patients with B-CLL, the immunoglobulin heavy-chain variable-region (IgVH) genes have undergone somatic mutations which can be identified by sequencing these genes. It has been shown that patients whose B-CLL cells express mutated Ig genes have a better prognosis than patients whose B-CLL cells express unmutated Ig genes (100% germline Ig identity) (Hallek et al., 2008). It has been shown that ZAP-70 is the most promising candidate marker to replace the need for IgVH studying for mutational status with a high predictive value (Chen, 2002). The role of ZAP70 in a B cell disease is unclear. B cells normally express PTK Syk instead of ZAP70. Syk and ZAP70 function downstream of Src-family kinases, which are PTKs such as Lck, Fyn and Lyn and the first tyrosine kinases to be activated after stimulation through the immunoreceptors (Mustelin et al., 2005). The phosphorylation of their targets provide binding sites for Syk and Zap70. As B-CLL cells are characterized by lower surface expression of IgM and CD79b than normal B lymphocytes, it is conceivable that association between ZAP-70 and CD79b may facilitate the recruitment of a Src kinase such as Lyn to the BCR complex, resulting in Lyn-mediated phosphorylation of the limiting numbers of ITAMs of CD79b following BCR ligation. Regardless of how ZAP-70 promotes BCR signaling in B-CLL, it is clear that its expression is associated with a worse prognosis. Expression of ZAP-70 is now being used clinically for prognostication.


Protein tyrosine phosphatases

PTPN6 or SHP-1 (SH2-domain-containing phosphatase-1) is a cytosolic key regulatory PTP that controls intracellular phosphotyrosine levels predominantly in hematopoietic cells of all lineages, but is also expressed at lower levels in epithelial cells (Lorenz, 2009). The human SHP-1 gene is located on chromosome 12p13 (Plutzky et al., 1992; Matsushita et al., 1999). It consists of 17 exons and spans approximately 17 kb of DNA with a transcription size of 2,4-2,6 kb (Wu et al., 2003). The SHP-1 gene encodes two forms of SHP-1 protein, with differences in the N-terminal, but with negligible activity as a result. Two different and mutually exclusive tissue-specific promoters regulate expression of the two forms of SHP-1 protein. Promoter 1 is active in all cells of non-hematopoietic origin, whereas promoter 2 is active exclusively in cells of hematopoietic lineage (Wu et al., 2003). Structurally, both SHP-1 and SHP-2 are composed of a central catalytic domain containing a specific PTP signature motif, two SH2 domains at their N-termini and a C-terminus (Poole and Jones, 2005). The SH2 domains are important for localization and activity regulation (Lorenz, 2009). The N-terminal SH2 domain is intramolecularly associated with the PTP domain, thereby repressing its activity. The repression is released when the SH2 domains are engaged, leading to activation of the phosphatase. Two tyrosines in the C-termini of SHP-1 (Y536 and Y564) and SHP-2 (Y542 and Y580) have been shown to become phosphorylated upon various stimuli which further influence the function and activities. Importantly, SHP-1 has also been proposed to have a role as a tumour-suppressor in lymphoma and leukaemia since decreased levels of both SHP-1 protein and mRNA have been observed in these malignancies (Wu et al., 2003). Moreover, SHP1 may be involved in the clinical evolution of myelodysplastic syndrome (MDS) (Mena-Duran, 2005). The role of SHP-1 in acute lymphoblastic leukaemia (ALL) has also been investigated, revealing that both SHP-1 and the tumor suppressor PTEN showed a significant difference in expression compared to nonmalignant controls (Gauffin et al., 2009). Studies also show that activated proliferation of B-cell lymphomas/leukemias with SHP1 gene silencing by aberrant CpG methylation (Koyama et al., 2003; Sato et al., 2010).

SHP-1 has been proposed as a candidate tumor suppressor gene since a decreased expression level of SHP-1 has been reported in several different types of haematological malignancies (Wu et al., 2003). Several mechanisms have been suggested for low expression level of SHP-1 protein and also SHP-1 mRNA in these malignancies: methylation of the promoter region of the SHP-1 gene or the post-transcriptional block of SHP-1 and also mutation of the SHP-1 gene. Taken together, SHP-1 protein has a central role in normal cell growth by regulating the activity of protein tyrosine kinases. Since the negative regulatory function of SHP-1 and its central role in many hematological malignancies has been suggested, it has been of great interest to find which molecules or substrates interact with SHP-1 protein. In this context, several different putative substrates for SHP-1 have been proposed. For instance, ZAP-70 and Syk have been proposed as potential substrates for SHP-1 in intact cells (Brockdorff et al., 1999).

Several other PTPs have been identified as the products of tumor suppressor genes (Tonks, 2006). One of the most studied is the PTP tumor suppressor, PTEN, a dual-specificity phosphatase, which is selective for dephosphorylating the critical phosphothreonine and phosphotyrosine residues. PTEN is short for "Phosphatase and tensin homologue deleted on chromosome 10", also referred to as "mutated in multiple advanced cancers" (MMAC1), and was discovered in 1997 (Li et al., 1997; Steck et al., 1997). PTEN is frequently inactivated in somatic cancers and is ranked the second most mutated tumour suppressor gene after p53 (Di Cristofano and Pandolfi, 2000; Georgescu, 2010). Loss of PTEN is seen in over half of all glioblastomata and in a high portion of breast and prostate cancer, in lymphomas and many other common malignancies (Tautz et al., 2009).

SHP-2, which is encoded by the PTPN11 gene was the first PTP with proven oncogenic function (Östman et al., 2006; Tonks, 2006). Gain-of-function mutations in SHP-2, initially identified as Noonan syndrome, facilitate activation of the PTP (Tartaglia et al., 2001). SHP-2 normally facilitates Ras activation by regulating the activity of Src-family PTKs, or the level of Sprouty proteins (Östman et al., 2006). Activating somatic mutations in the gene PTPN11 have been associated with increased risk of certain sporadic childhood malignancies, such as juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML), which induce hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) in hematopoietic progenitor cells (Östman et al., 2006). Upon transplantation into lethally-irradiated mice, bone marrow expressing leukemia-associated SHP-2 mutants give rise to a fatal invasive myeloproliferative disease that is associated with hyperactivation of the mitogen-activated protein kinase (MAPK) Erk and other signalling pathways (Mohi et al., 2005). The LEOPARD syndrome shares clinical features with the Noonan syndrome, but is instead associated with mutations that act as dominant negatives and interfere with Erk MAPK activation (Kontaridis et al., 2006).

Except for SHP-2, one more intracellular PTPs has been shown to have positive regulatory function, namely low molecular weight protein tyrosine phosphatases (LMW-PTP) (Mustelin et al., 2005). LMW-PTP dephosphorylates the negative regulatory site Y292 of PTK Zap70, which results in a slower down-modulation of cell surface T cell receptor (TCR) (Bottini et al., 2002a). Acid phosphatase locus 1 (ACP1) is a polymorphic gene located on chromosome 2 showing three common codominant alleles: ACP1A, ACP1B and ACP1C (Hopkinson et al., 1963; Bottini et al., 1995). The corresponding 6 genotypes are associated with different enzymatic activities (Spencer et al., 1964). The ACPs, or LMW-PTPs, are a group of tyrosine phosphatases expressed in certain tissue including glandular cells of different tissue as well as lymphocytes, breast, colon, brain, gastric ventricle and prostate. LMW-PTP has been characterized as tyrosine, but not a serine or threonine phosphatase (Malentacchi et al., 2005). In humans, LMW-PTP is expressed by a single copy gene located on chromosome 2. The primary transcript shows a complex pattern of alternative splicing which leads to the production of four different mRNAs. The role of LMW-PTP in cell proliferation seems to be important and is carried out by dephosphorylation leading to inactivation of tyrosine kinases such as the insulin-receptor, platelet- derived growth factor-receptor (PDGF-R), the ephrin receptor and docking proteins such as β-catenin having both adhesion and transcription activity (Chiarugi et al., 2002; Chiarugi et al., 2004). The enzyme interacts with several receptors and proteins and is involved in the regulation of Jak/STAT, which is one of the signaling pathways that is often dysregulated in leukemias. Moreover, the JAK-gene is linked to some hematopoietic malignancies. Inhibition of LMW-PTP results in a partly increased and prolonged phosphorylation of JAK/STAT as well as a decrease in apoptosis. Oxidation of the enzyme also leads to anti-apoptotic effects. Over-expression of LMW-PTP has been shown to counteract malign transformation and signaling of tyrosine kinase oncogenes. Moreover, over-expression of LMW-PTP is also associated with several cancer forms (Bottini et al., 2002b; Alho et al., 2008).

Hematopoietic phosphatase (HePTP), PTPN7, is the only pTyr-specific PTP known to dephosphorylate MAPKs in hematopoietic cells (Saxena et al., 1999; Sergienko et al., 2012). HePTP is a 38-kDa enzyme, consisting of the C-terminal catalytic PTP domain and a short (45 residues) N-terminal extension, which contains the kinase interaction motif (KIM, residues 15-31) (Zanke et al., 1992; Zanke et al., 1994; Adachi et al., 1994). The first indication of a role of HePTP in cell proliferation or differentiation came from the finding that the HePTP gene is located on the long arm of chromosome 1, which is often found in extra copies (trisomy) in bone marrow cells from patients with MDS, which is characterized by reduced hematopoiesis and increased risk of acute leukemia. Indeed, amplification and overexpression of HePTP is also reported in cases of acute myeloid leukemia (AML) (Saxena et al., 1999). HePTP is down-regulated in pediatric lymphoma compared to control lymphoid cells (Fridberg et al., 2008). Loss of HePTP might indicate increased cell proliferation and/or survival of lymphoma cells.

T-cell phosphatase (TC-PTP), PTPN2, (Mosinger et al., 1992) is described as a phosphatase for both JAKs and STATs, which are important signaling proteins downstream of cytokine receptors (Kleppe et al., 2011). TC-PTP has been shown to be a tumor suppressor gene in T-cell malignancies (Kleppe, 2010; Kleppe, 2011). Moreover, TC-PTP was identified as a physiological regulator of STAT6 phosphorylation in ABC-like DLBCLs, which may contribute to the different biological characteristics of these DLBCL tumors (Lu et al., 2007).


Summary and conclusion

Many PTKs have already been discovered as drug targets and the treatment of many human diseases. Also PTPs will be found to be involved in human diseases and will be used as drug targets to treat these diseases in the future. However, there is a great need to investigate interactions between factors which are likely of pathogenic importance to develop new therapeutics for patients with lymphoma and/or leukemia. Moreover, establishing laboratory tests which are sufficiently sensitive and specific to be prognostic for these patients might influence management decisions for determining the best course of treatment.


Nature. 1963 Sep 7;199:969-71.
PMID 14073798
Nature. 1964 Jan 18;201:299-300.
PMID 14110459
Restriction of the in vitro and in vivo tyrosine protein kinase activities of pp60c-src relative to pp60v-src.
Coussens PM, Cooper JA, Hunter T, Shalloway D.
Mol Cell Biol. 1985 Oct;5(10):2753-63.
PMID 2426575
A lymphocyte-specific protein-tyrosine kinase gene is rearranged and overexpressed in the murine T cell lymphoma LSTRA.
Marth JD, Peet R, Krebs EG, Perlmutter RM.
Cell. 1985 Dec;43(2 Pt 1):393-404.
PMID 2416464
Location of the c-yes gene on the human chromosome and its expression in various tissues.
Semba K, Yamanashi Y, Nishizawa M, Sukegawa J, Yoshida M, Sasaki M, Yamamoto T, Toyoshima K.
Science. 1985 Mar 1;227(4690):1038-40.
PMID 2983418
Localization of a lymphocyte-specific protein tyrosine kinase gene (lck) at a site of frequent chromosomal abnormalities in human lymphomas.
Marth JD, Disteche C, Pravtcheva D, Ruddle F, Krebs EG, Perlmutter RM.
Proc Natl Acad Sci U S A. 1986 Oct;83(19):7400-4.
PMID 3463975
The yes-related cellular gene lyn encodes a possible tyrosine kinase similar to p56lck.
Yamanashi Y, Fukushige S, Semba K, Sukegawa J, Miyajima N, Matsubara K, Yamamoto T, Toyoshima K.
Mol Cell Biol. 1987 Jan;7(1):237-43.
PMID 3561390
Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin.
Ziegler SF, Marth JD, Lewis DB, Perlmutter RM.
Mol Cell Biol. 1987 Jun;7(6):2276-85.
PMID 3453117
Specific expression of a tyrosine kinase gene, blk, in B lymphoid cells.
Dymecki SM, Niederhuber JE, Desiderio SV.
Science. 1990 Jan 19;247(4940):332-6.
PMID 2404338
The zeta chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein.
Chan AC, Irving BA, Fraser JD, Weiss A.
Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9166-70.
PMID 1717999
Identification, cloning, and expression of a cytosolic megakaryocyte protein-tyrosine-phosphatase with sequence homology to cytoskeletal protein 4.1.
Gu MX, York JD, Warshawsky I, Majerus PW.
Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5867-71.
PMID 1648233
Molecular characterization of a protein-tyrosine-phosphatase enriched in striatum.
Lombroso PJ, Murdoch G, Lerner M.
Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7242-6.
PMID 1714595
Effect of protein tyrosine phosphatase 1B expression on transformation by the human neu oncogene.
Brown-Shimer S, Johnson KA, Hill DE, Bruskin AM.
Cancer Res. 1992 Jan 15;52(2):478-82.
PMID 1345814
Cloning and characterization of a mouse cDNA encoding a cytoplasmic protein-tyrosine-phosphatase.
Mosinger B Jr, Tillmann U, Westphal H, Tremblay ML.
Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):499-503.
PMID 1731319
Chromosomal localization of an SH2-containing tyrosine phosphatase (PTPN6).
Plutzky J, Neel BG, Rosenberg RD, Eddy RL, Byers MG, Jani-Sait S, Shows TB.
Genomics. 1992 Jul;13(3):869-72.
PMID 1639416
Assignment of tyrosine-specific T-cell phosphatase to conserved syntenic groups on human chromosome 18 and mouse chromosome 18.
Sakaguchi AY, Sylvia VL, Martinez L, Smith EA, Han ES, Lalley PA, Shows TB, Choudhury GG.
Genomics. 1992 Jan;12(1):151-4.
PMID 1733852
Cloning and characterization of a human cDNA encoding a novel putative cytoplasmic protein-tyrosine-phosphatase.
Takekawa M, Itoh F, Hinoda Y, Arimura Y, Toyota M, Sekiya M, Adachi M, Imai K, Yachi A.
Biochem Biophys Res Commun. 1992 Dec 15;189(2):1223-30.
PMID 1472029
Cloning and expression of an inducible lymphoid-specific, protein tyrosine phosphatase (HePTPase).
Zanke B, Suzuki H, Kishihara K, Mizzen L, Minden M, Pawson A, Mak TW.
Eur J Immunol. 1992 Jan;22(1):235-9.
PMID 1530918
Expression and chromosomal assignment of PTPH1 gene encoding a cytosolic protein tyrosine phosphatase homologous to cytoskeletal-associated proteins.
Itoh F, Ikuta S, Hinoda Y, Arimura Y, Ohe M, Adachi M, Ariyama T, Inazawa J, Imai K, Yachi A.
Int J Cancer. 1993 Dec 2;55(6):947-51.
PMID 8253532
Structure of the human LC-PTP (HePTP) gene: similarity in genomic organization within protein-tyrosine phosphatase genes.
Adachi M, Miyachi T, Sekiya M, Hinoda Y, Yachi A, Imai K.
Oncogene. 1994 Oct;9(10):3031-5.
PMID 8084610
Dual myristylation and palmitylation of Src family member p59fyn affects subcellular localization.
Alland L, Peseckis SM, Atherton RE, Berthiaume L, Resh MD.
J Biol Chem. 1994 Jun 17;269(24):16701-5.
PMID 8206991
Chromosomal localization of an SH2 containing tyrosine phosphatase (SH-PTP3) gene to chromosome 12q24.1.
Isobe M, Hinoda Y, Imai K, Adachi M.
Oncogene. 1994 Jun;9(6):1751-3.
PMID 8183573
Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans.
Ku G, Malissen B, Mattei MG.
Immunogenetics. 1994;40(4):300-2.
PMID 8082894
Molecular cloning and analysis of the human Tec protein-tyrosine kinase.
Sato K, Mano H, Ariyama T, Inazawa J, Yazaki Y, Hirai H.
Leukemia. 1994 Oct;8(10):1663-72.
PMID 7934162
A hematopoietic protein tyrosine phosphatase (HePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome 1q32.1.
Zanke B, Squire J, Griesser H, Henry M, Suzuki H, Patterson B, Minden M, Mak TW.
Leukemia. 1994 Feb;8(2):236-44.
PMID 8309248
ACP1 and human adaptability. 1. Association with common diseases: a case-control study.
Bottini E, Gloria-Bottini F, Borgiani P.
Hum Genet. 1995 Dec;96(6):629-37.
PMID 8522318
Murine protein tyrosine phosphatase-PEST, a stable cytosolic protein tyrosine phosphatase.
Charest A, Wagner J, Shen SH, Tremblay ML.
Biochem J. 1995 Jun 1;308 ( Pt 2):425-32.
PMID 7772023
Protein-tyrosine phosphatase SH-PTP2 (PTPN11) is localized to 12q24.1-24.3.
Dechert U, Duncan AM, Bastien L, Duff C, Adam M, Jirik FR.
Hum Genet. 1995 Nov;96(5):609-15.
PMID 8530013
The Btk subfamily of cytoplasmic tyrosine kinases: structure, regulation and function.
Rawlings DJ, Witte ON.
Semin Immunol. 1995 Aug;7(4):237-46.
PMID 8520028
PTPN13, a fas-associated protein tyrosine phosphatase, is located on the long arm of chromosome 4 at band q21.3.
Inazawa J, Ariyama T, Abe T, Druck T, Ohta M, Huebner K, Yanagisawa J, Reed JC, Sato T.
Genomics. 1996 Jan 15;31(2):240-2.
PMID 8824809
The gene (PTPN13) encoding the protein tyrosine phosphatase PTP-BL/PTP-BAS is located in mouse chromosome region 5E/F and human chromosome region 4q21.
van den Maagdenberg AM, Olde Weghuis D, Rijss J, Merkx GF, Wieringa B, Geurts van Kessel A, Hendriks WJ.
Cytogenet Cell Genet. 1996;74(1-2):153-5.
PMID 8893825
PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R.
Science. 1997 Mar 28;275(5308):1943-7.
PMID 9072974
Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.
Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV.
Nat Genet. 1997 Apr;15(4):356-62.
PMID 9090379
Cellular functions regulated by Src family kinases.
Thomas SM, Brugge JS.
Annu Rev Cell Dev Biol. 1997;13:513-609. (REVIEW)
PMID 9442882
The Syk family of protein tyrosine kinases in T-cell activation and development.
Chu DH, Morita CT, Weiss A.
Immunol Rev. 1998 Oct;165:167-80.
PMID 9850860
Fyn, a Src family tyrosine kinase.
Resh MD.
Int J Biochem Cell Biol. 1998 Nov;30(11):1159-62. (REVIEW)
PMID 9839441
The many faces of Src: multiple functions of a prototypical tyrosine kinase.
Schwartzberg PL.
Oncogene. 1998 Sep 17;17(11 Reviews):1463-8. (REVIEW)
PMID 9779992
Peptide and protein phosphorylation by protein tyrosine kinase Csk: insights into specificity and mechanism.
Sondhi D, Xu W, Songyang Z, Eck MJ, Cole PA.
Biochemistry. 1998 Jan 6;37(1):165-72.
PMID 9425036
Dephosphorylation of ZAP-70 and inhibition of T cell activation by activated SHP1.
Brockdorff J, Williams S, Couture C, Mustelin T.
Eur J Immunol. 1999 Aug;29(8):2539-50.
PMID 10458769
Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp.
Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM.
Blood. 1999 Mar 15;93(6):2013-24.
PMID 10068674
New variations of human SHP-1.
Matsushita M, Tsuchiya N, Oka T, Yamane A, Tokunaga K.
Immunogenetics. 1999 Jun;49(6):577-9.
PMID 10380707
The next wave: protein tyrosine phosphatases enter T cell antigen receptor signalling.
Mustelin T, Brockdorff J, Rudbeck L, Gjorloff-Wingren A, Han S, Wang X, Tailor P, Saxena M.
Cell Signal. 1999 Sep;11(9):637-50. (REVIEW)
PMID 10530872
Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP).
Saxena M, Williams S, Brockdorff J, Gilman J, Mustelin T.
J Biol Chem. 1999 Apr 23;274(17):11693-700.
PMID 10206983
Src family tyrosine kinases and growth factor signaling.
Abram CL, Courtneidge SA.
Exp Cell Res. 2000 Jan 10;254(1):1-13. (REVIEW)
PMID 10623460
The multiple roles of PTEN in tumor suppression.
Di Cristofano A, Pandolfi PP.
Cell. 2000 Feb 18;100(4):387-90. (REVIEW)
PMID 10693755
Genomic characterization of the human and mouse protein tyrosine phosphatase-1B genes.
Forsell PA, Boie Y, Montalibet J, Collins S, Kennedy BP.
Gene. 2000 Dec 30;260(1-2):145-53.
PMID 11137300
Subcellular localization of intracellular protein tyrosine phosphatases in T cells.
Gjorloff-Wingren A, Saxena M, Han S, Wang X, Alonso A, Renedo M, Oh P, Williams S, Schnitzer J, Mustelin T.
Eur J Immunol. 2000 Aug;30(8):2412-21.
PMID 10940933
Tec family kinases in lymphocyte signaling and function.
Schaeffer EM, Schwartzberg PL.
Curr Opin Immunol. 2000 Jun;12(3):282-8.
PMID 10781397
Tyrosine kinase SYK: essential functions for immunoreceptor signalling.
Turner M, Schweighoffer E, Colucci F, Di Santo JP, Tybulewicz VL.
Immunol Today. 2000 Mar;21(3):148-54. (REVIEW)
PMID 10689303
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.
Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD.
Nat Genet. 2001 Dec;29(4):465-8.
PMID 11704759
World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues.
Jaffe ES, Harris NL, Stein H, Vardiman JW, editors.
Lyon, France: IARC; 2001.
Activation of ZAP-70 through specific dephosphorylation at the inhibitory Tyr-292 by the low molecular weight phosphotyrosine phosphatase (LMPTP).
Bottini N, Stefanini L, Williams S, Alonso A, Jascur T, Abraham RT, Couture C, Mustelin T.
J Biol Chem. 2002a Jul 5;277(27):24220-4. Epub 2002 Apr 25.
PMID 11976341
Low-molecular-weight protein tyrosine phosphatase and human disease: in search of biochemical mechanisms.
Bottini N, Bottini E, Gloria-Bottini F, Mustelin T.
Arch Immunol Ther Exp (Warsz). 2002b;50(2):95-104. (REVIEW)
PMID 12022706
Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia.
Chen L, Widhopf G, Huynh L, Rassenti L, Rai KR, Weiss A, Kipps TJ.
Blood. 2002 Dec 15;100(13):4609-14. Epub 2002 Aug 8.
PMID 12393534
Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation.
Chiarugi P, Cirri P, Taddei ML, Giannoni E, Fiaschi T, Buricchi F, Camici G, Raugei G, Ramponi G.
J Biol Chem. 2002 Oct 4;277(40):37331-8. Epub 2002 Jul 30.
PMID 12149261
The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma.
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM; Lymphoma/Leukemia Molecular Profiling Project.
N Engl J Med. 2002 Jun 20;346(25):1937-47.
PMID 12075054
Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning.
Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC, Gaasenbeek M, Angelo M, Reich M, Pinkus GS, Ray TS, Koval MA, Last KW, Norton A, Lister TA, Mesirov J, Neuberg DS, Lander ES, Aster JC, Golub TR.
Nat Med. 2002 Jan;8(1):68-74.
PMID 11786909
Activated proliferation of B-cell lymphomas/leukemias with the SHP1 gene silencing by aberrant CpG methylation.
Koyama M, Oka T, Ouchida M, Nakatani Y, Nishiuchi R, Yoshino T, Hayashi K, Akagi T, Seino Y.
Lab Invest. 2003 Dec;83(12):1849-58.
PMID 14691303
The function of the protein tyrosine phosphatase SHP-1 in cancer.
Wu C, Sun M, Liu L, Zhou GW.
Gene. 2003 Mar 13;306:1-12.
PMID 12657462
Protein tyrosine phosphatases in the human genome.
Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T.
Cell. 2004 Jun 11;117(6):699-711. (REVIEW)
PMID 15186772
A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage.
Andersen JN, Jansen PG, Echwald SM, Mortensen OH, Fukada T, Del Vecchio R, Tonks NK, Moller NP.
FASEB J. 2004 Jan;18(1):8-30.
PMID 14718383
LMW-PTP is a positive regulator of tumor onset and growth.
Chiarugi P, Taddei ML, Schiavone N, Papucci L, Giannoni E, Fiaschi T, Capaccioli S, Raugei G, Ramponi G.
Oncogene. 2004 May 13;23(22):3905-14.
PMID 15021900
Up-regulated expression of low molecular weight protein tyrosine phosphatases in different human cancers.
Malentacchi F, Marzocchini R, Gelmini S, Orlando C, Serio M, Ramponi G, Raugei G.
Biochem Biophys Res Commun. 2005 Sep 2;334(3):875-83.
PMID 16036221
SHP1 expression in bone marrow biopsies of myelodysplastic syndrome patients: a new prognostic factor.
Mena-Duran AV, Togo SH, Bazhenova L, Cervera J, Bethel K, Senent ML, Nieva J, Sanz GF, Sanz MA, Saven A, Mustelin T.
Br J Haematol. 2005 Jun;129(6):791-4.
PMID 15953006
Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations.
Mohi MG, Williams IR, Dearolf CR, Chan G, Kutok JL, Cohen S, Morgan K, Boulton C, Shigematsu H, Keilhack H, Akashi K, Gilliland DG, Neel BG.
Cancer Cell. 2005 Feb;7(2):179-91.
PMID 15710330
Protein tyrosine phosphatases and the immune response.
Mustelin T, Vang T, Bottini N.
Nat Rev Immunol. 2005 Jan;5(1):43-57. (REVIEW)
PMID 15630428
A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail.
Poole AW, Jones ML.
Cell Signal. 2005 Nov;17(11):1323-32. (REVIEW)
PMID 16084691
PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.
Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG.
J Biol Chem. 2006 Mar 10;281(10):6785-92. Epub 2005 Dec 23.
PMID 16377799
Protein-tyrosine phosphatases and cancer.
Ostman A, Hellberg C, Bohmer FD.
Nat Rev Cancer. 2006 Apr;6(4):307-20. (REVIEW)
PMID 16557282
Targeting the PTPome in human disease.
Tautz L, Pellecchia M, Mustelin T.
Expert Opin Ther Targets. 2006 Feb;10(1):157-77. (REVIEW)
PMID 16441235
Protein tyrosine phosphatases: from genes, to function, to disease.
Tonks NK.
Nat Rev Mol Cell Biol. 2006 Nov;7(11):833-46. (REVIEW)
PMID 17057753
Comparative analysis of flow cytometric techniques in assessment of ZAP-70 expression in relation to IgVH mutational status in chronic lymphocytic leukemia.
Chen YH, Peterson LC, Dittmann D, Evens A, Rosen S, Khoong A, Shankey TV, Forman M, Gupta R, Goolsby CL.
Am J Clin Pathol. 2007 Feb;127(2):182-91.
PMID 17210531
ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells.
Gobessi S, Laurenti L, Longo PG, Sica S, Leone G, Efremov DG.
Blood. 2007 Mar 1;109(5):2032-9. Epub 2006 Oct 12.
PMID 17038529
T-cell protein tyrosine phosphatase, distinctively expressed in activated-B-cell-like diffuse large B-cell lymphomas, is the nuclear phosphatase of STAT6.
Lu X, Chen J, Sasmono RT, Hsi ED, Sarosiek KA, Tiganis T, Lossos IS.
Mol Cell Biol. 2007 Mar;27(6):2166-79. Epub 2007 Jan 8.
PMID 17210636
Low molecular weight protein tyrosine phosphatase genetic polymorphism and susceptibility to cancer development.
Alho I, Clara Bicho M, Carvalho R, da Silva AP, Costa L, Bicho M.
Cancer Genet Cytogenet. 2008 Feb;181(1):20-4.
PMID 18262048
ZAP-70 enhances IgM signaling independent of its kinase activity in chronic lymphocytic leukemia.
Chen L, Huynh L, Apgar J, Tang L, Rassenti L, Weiss A, Kipps TJ.
Blood. 2008 Mar 1;111(5):2685-92. Epub 2007 Nov 29.
PMID 18048647
Immunohistochemical analyses of phosphatases in childhood B-cell lymphoma: lower expression of PTEN and HePTP and higher number of positive cells for nuclear SHP2 in B-cell lymphoma cases compared to controls.
Fridberg M, Kjellstrom S, Anagnostaki L, Skogvall I, Mustelin T, Wiebe T, Persson JL, Dictor M, Wingren AG.
Pediatr Hematol Oncol. 2008 Sep;25(6):528-40.
PMID 18728972
Prognostic factors in chronic lymphocytic leukemia.
Hallek M; German CLL Study Group.
Ann Oncol. 2008 Jun;19 Suppl 4:iv51-3. (REVIEW)
PMID 18519404
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.
Swerdlow SH, Campo E, Harris NL, et al, editors.
Lyon, France: IARC; 2008.
Diffuse large B-cell lymphomas and burkitt lymphoma.
de Leval L, Hasserjian RP.
Hematol Oncol Clin North Am. 2009 Aug;23(4):791-827. (REVIEW)
PMID 19577170
Expression of PTEN and SHP1, investigated from tissue microarrays in pediatric acute lymphoblastic, leukemia.
Gauffin F, Diffner E, Gustafsson B, Nordgren A, Wingren AG, Sander B, Persson JL, Gustafsson B.
Pediatr Hematol Oncol. 2009 Jan;26(1):48-56.
PMID 19206008
SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels.
Lorenz U.
Immunol Rev. 2009 Mar;228(1):342-59. (REVIEW)
PMID 19290938
The Src, Syk, and Tec family kinases: distinct types of molecular switches.
Bradshaw JM.
Cell Signal. 2010 Aug;22(8):1175-84. Epub 2010 Mar 4. (REVIEW)
PMID 20206686
PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control.
Georgescu MM.
Genes Cancer. 2010 Dec;1(12):1170-7.
PMID 21779440
Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia.
Kleppe M, Lahortiga I, El Chaar T, De Keersmaecker K, Mentens N, Graux C, Van Roosbroeck K, Ferrando AA, Langerak AW, Meijerink JP, Sigaux F, Haferlach T, Wlodarska I, Vandenberghe P, Soulier J, Cools J.
Nat Genet. 2010 Jun;42(6):530-5. Epub 2010 May 16.
PMID 20473312
Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma.
Sato H, Oka T, Shinnou Y, Kondo T, Washio K, Takano M, Takata K, Morito T, Huang X, Tamura M, Kitamura Y, Ohara N, Ouchida M, Ohshima K, Shimizu K, Tanimoto M, Takahashi K, Matsuoka M, Utsunomiya A, Yoshino T.
Am J Pathol. 2010 Jan;176(1):402-15. Epub 2009 Dec 17.
PMID 20019193
ZAP-70: an essential kinase in T-cell signaling.
Wang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu LY, Freedman TS, Weiss A.
Cold Spring Harb Perspect Biol. 2010 May;2(5):a002279. (REVIEW)
PMID 20452964
Mutation analysis of the tyrosine phosphatase PTPN2 in Hodgkin's lymphoma and T-cell non-Hodgkin's lymphoma.
Kleppe M, Tousseyn T, Geissinger E, Kalender Atak Z, Aerts S, Rosenwald A, Wlodarska I, Cools J.
Haematologica. 2011 Nov;96(11):1723-7. Epub 2011 Jul 26.
PMID 21791476
Inhibition of hematopoietic protein tyrosine phosphatase augments and prolongs ERK1/2 and p38 activation.
Sergienko E, Xu J, Liu WH, Dahl R, Critton DA, Su Y, Brown BT, Chan X, Yang L, Bobkova EV, Vasile S, Yuan H, Rascon J, Colayco S, Sidique S, Cosford ND, Chung TD, Mustelin T, Page R, Lombroso PJ, Tautz L.
ACS Chem Biol. 2012 Feb 17;7(2):367-77. doi: 10.1021/cb2004274. Epub 2011 Nov 17.
PMID 22070201
Written2012-03Payam Delfani, Anette Gjörloff Wingren
of Immunotechnology, Lund University, Lund, Sweden (PD); Department of Biomedical Sciences, Health, Society, Malmo University, Sweden (AGW)


This paper should be referenced as such :
Delfani, P ; Gjörloff, Wingren A
Intracellular tyrosine phosphatases, kinases in lymphoma
Atlas Genet Cytogenet Oncol Haematol. 2012;16(8):594-601.
Free journal version : [ pdf ]   [ DOI ]
On line version :