Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

ZAP70 (zeta-chain (TCR) associated protein kinase 70kDa)

Written2015-09Payam Delfani1, Zahra El-Schich2 and Anette Gjörloff Wingren

Abstract Review on ZAP70, with data on DNA, on the protein encoded, and where the gene is implicated.

(Note : for Links provided by Atlas : click)


Other namesSRK
HGNC (Hugo) ZAP70
LocusID (NCBI) 7535
Atlas_Id 197
Location 2q11.2
Location_base_pair Starts at 98330031 and ends at 98356323 bp from pter ( according to hg19-Feb_2009)  [Mapping]


Description The ZAP70 gene encodes an enzyme belonging to the protein tyrosine kinase (PTK) family, and it plays a role in T-cell development and lymphocyte activation. The cDNA clone encoding human ZAP70 was identified for the first time by Chan et al. in 1992 (Chan 1992), and mouse cDNA for both ZAP70 and Syk was cloned two years later (Ku 1994). Mutations in this gene cause selective T-cell defect, a severe combined immunodeficiency (SCID) disease characterized by a selective absence of CD8-positive T-cells (review in Wang 2010).
Transcription The transcript encodes 619 amino acids with a mass of 69,872 Da. Three isoforms have been described ( Isoform 1 (full-length); Isoform 2 (1-307 is missing); Isoform 3 (1-126 is missing; 127-134 VRQTWKLE->MRLGPRWK).


  Figure 1. Schematic structure of inactive ZAP70 (adopted from Wang et al 2010). he ZAP70 domains indicated are the amino-terminal SH2 domain (N-SH2), interdomain A (I-A), carboxy-terminal SH2 domain (C-SH2), interdomain B (I-B) and the kinase domain.
Description ZAP70 is composed of two SH2 domains and a carboxy-terminal kinase domain (Fig. 1). The crystal structure of the tandem SH2 domains of the human PTK ZAP70 in complex with a peptide derived from the zeta-subunit of the T-cell receptor (TCR) was revealed by Hatada et al (Hatada 1995). A coiled coil of alpha-helices connects the two SH2 domains, producing an interface that constitutes one of the two critical phosphotyrosine binding sites, providing the molecular basis for highly selective association of ZAP70 with the T-cell receptor. The crystal structure of autoinhibited ZAP70 revealed a new mechanism for maintaining an inactive kinase domain conformation (Deindl 2007), which also have been shown in cell-based experiments (Brdicka 2005; Deindl 2009). The two tandem SH2 domains that are separated by a linker region, termed interdomain A. Upon activation, conformational changes in ZAP70 promote disassembly of the interface mediating the autoinhibited conformation, and exposure of tyrosines Y292, Y315 and Y319 in interdomain B, leading to their phosphorylation that further destabilizes the interface (Wang 2010).
Expression ZAP70 protein is expressed in all major thymocyte populations, with the level of expression being comparable to that found in both CD4+ and CD8+ peripheral T cells (Chan 1991;Irving 1993). Stimulation of the TCR results in tyrosine phosphorylation of a number of cellular substrates. One of these is the TCR zeta chain, which can mediate the transduction of extracellular stimuli into cellular effector functions. When ZAP70 was discovered, it represented a novel PTK and was found to be expressed in T cells and natural killer (NK) cells. The tyrosine phosphorylation and association of ZAP70 with TCR zeta was shown to require the presence of src family PTKs and provide a potential mechanism by which the src family PTKs and ZAP70 may interact to mediate TCR signal transduction (Chan 1991;Irving 1993).
The first indication that ZAP70 may be expressed in the B cell lineage came from studies of B-cell chronic lymphocytic leukemia (CLL) (Rosenwald 2001). ZAP70 was thereafter also reported to be expressed throughout B cell development at different maturational stages and that it plays a role in the transition of pro-B to pre-B cells in the bone marrow, a checkpoint controlled by signals from the pre-B cell receptor (pre-BCR), which monitors for successful rearrangement of immunoglobulin heavy chain genes (Schweighoffer 2003; Nolz 2005; Crespo 2006; Scielzo 2006).
Localisation In the cytoplasmic compartment of the T-cell, once recruited to tyrosines in the immunoreceptor tyrosine-based activation motif (ITAM) of the TCR-subunit, ZAP70 is activated by phosphorylation, at Tyr-493 in its activation loop, by Lck (Chan 1995; Wange 1995). Upon phosphorylation, these bound ZAP70 molecules autophosphorylate to create docking sites for SH2-domain-containing signalling proteins (Neumeister 1995; Katzav 1994; Couture 1994; Duplay 1994). Docking of ZAP70 at the plasma membrane is required for its activation (reviewed in Fischer 2010).
Function Indeed, PTKs play an integral role in T cell activation. TCR signal transduction and the events leading to activation of downstream signaling pathways involve many molecules, including the PTKs Src, Syk, Csk and Tec families, as well as adaptor proteins and effector enzymes in tyrosine phosphorylation cascades (review in Mustelin, 2003). Both SH2-domains of ZAP70 are crucial for high avidity binding and for function in signal transduction (Bu 1995; review by Au-Yeung 2009 and Wang 2010). ZAP70 is phosphorylated on tyrosine residues upon TCR stimulation, and functions in the initial step of TCR-mediated signal transduction in combination with the clustering of coreceptor (CD4 or CD8)-associated LCK with T cell receptors allows Lck to phosphorylate tyrosine residues in ITAMs in the intracellular tails of zeta chains of the TCR-complex (Yan 2013). Doubly phosphorylated ITAMs in the stimulated TCR complex recruit ZAP-70 to the plasma membrane. Activated ZAP70 subsequently phosphorylates at least two critically important adaptor proteins, linker for the activation of T cells (LAT) and SH2-domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76 ) (Bubeck Wardenburg 1996; Zhang 1998; Au-Yeung 2009). Interdomain B in the ZAP70 molecule, between the C-terminal SH2-domain and the kinase domain, is also a critical region because of the three tyrosine residues Y292, Y315 and Y319 that are phosphorylated by Lck upon TCR-triggering (Fischer 2010). The tyrosine Y292 binds the ubiquitin ligase c-Cbl and control both zeta (of the TCR-CD3-zeta complex) ubiquitination and TCR downmodulation, whereas Y315 interacts with the CT10 regulator of kinase II (CrkII ) adapter protein (Lupher 1997; Gelkop 1999; Fischer 2010). The tyrosine Y319 is also a binding site for CC: TXT: PLC-gamma ID: 44163> , resulting in a positive ZAP70 kinase-mediated regulation through PLC-gamma phosphorylation and Ca2+ mobilization (Di Bartolo 1999; Williams 1999). The kinase domain itself also contains two tyrosine residues that are phosphorylated. Phosphorylation of Y493 by Src-family PTKs upregulate ZAP70 activity, whereas phosphorylation of Y492 seems to do the opposite, by negatively regulate ZAP70 kinase activity (Chan 1995; Wange 1995). Moreover, the low molecular weight protein-tyrosine phosphatase (LMPTP) specifically dephosphorylates the negative regulatory Tyr-292 of ZAP-70, thereby counteracting inactivation of ZAP70 (Bottini 2002). The proteins phosphorylated by ZAP70 are not that well investigated. VHR , a Vaccinia virus VH-1 related dual-specific protein phosphatase that inactivates the mitogen-activated kinases Erk1 and Jnk, is phosphorylated at Y138 by ZAP70 (Alonso 2002).
The role of ZAP70 in B cells have been investigated, but is poorly understood possibly due to the functional redundancy between Syk and ZAP70 (Fallah-Arani 2008). Studies in CLL reveal that the ability of ZAP70 to enhance BCR signalling was independent of its kinase activity as both WT ZAP70 and a catalytically inactive ZAP70 mutant induced similar increases in intracellular free Ca2+ concentration upon BCR triggering (Chen 2008).
Homology Together with Syk, ZAP70 defines the Syk family of PTKs, with structural homology composed of non-myristylated cytoplasmic peptides of two N-terminal Src-homology 2 (SH2) domains and a C-terminal catalytic domain (Taniguchi 1991; Chan 1992). Although Syk protein is also present in all thymocyte subsets, expression of Syk protein is down-regulated three- to fourfold in peripheral T cells. In contrast to ZAP70, expression of Syk is 12- to 15-fold higher in peripheral B cells when compared with peripheral T cells (Chan 1994a). Both ZAP-70 and Syk are dependent upon a Src-family protein tyrosine kinase for association with the phosphorylated zeta-chain. Thus, the differential expression of these kinases suggests the possibility of different roles for ZAP70 and Syk in TCR signaling and thymic development (Palacios 2007). Another study showed functional homology in antigen receptor signaling by demonstrating that expression of ZAP70 in Syk- B cells reconstitutes BCR function (Kong 1995). Reconstitution required the presence of functional Src homology 2 (SH2) and catalytic domains of ZAP70. In addition, they demonstrated that both ZAP70 and Syk can bind directly to the phosphorylated Ig alpha and Ig beta subunits with affinities comparable to their binding to the TCR CD3 epsilon subunit (Kong 1995). Another feature that distinguish ZAP70 from Syk is its greater dependency on Src kinases for activation and its ability to phosphorylate and promote the auto-activation of the downstream mitogen-activated protein kinase (MAPK) p38 (reviewed in Au-Yeung 2009).


Somatic ZAP70 base mutation registry for ZAP70 deficiency. ZAP70 deficiency is a rare autosomal recessive form of severe combined immunodeficiency characterized by the selective absence of CD8+ T cells and by abundant CD4+ T cells in the peripheral blood that are unresponsive to TCR-mediated stimuli in vitro ( The first rare ZAP70 mutations in humans were discovered before mouse models were established. The rare ZAP70 mutations in humans have been described in about 20 patients from different families (Arpaia 1994; Elder 1994; Chan 1994b; review in Fischer 2010 and Karaca 2013). All patients that were reported with complete deficiency in ZAP70 activity presented with severe clinical phenotype similar to severe combined immunodeficiency. ZAP70 mutations occurring in human SCID are mostly located in the kinase domain, but mutations causing transcriptional loss of ZAP70 or destabilization of the protein have also been reported. Elder et al reported that a patient with a missense mutation within the highly conserved DLAARN motif of the kinase domain (Elder 2001). Other examples are described by Fischer et al and by Karaca et al showing a lack or absence of CD8-positive T cells, high numbers of nonfunctional CD4-positive T cells, but normal numbers of B cells, with some patients having normal or elevated serum immunoglobulins (Ig) levels and defective antibody production (Matsuda 1999; Noraz 2000; Meinl 2000; Turul 2009; Picard 2009; review in Fischer 2010 and Karaca 2013).

Implicated in

Entity Severe combined immunodeficiency (SCID)
Note Lack of ZAP70 in humans leads to a severe immunodeficiency characterized by the absence of CD8+ T-cells and TCR-unresponsive mature CD4+ T-cells. Mice lacking ZAP70 are also deficient in the production of CD4+ T-cells, while the natural killer cells are unaffected (Arpaia 1994; Elder 1994; Chan 1994b; Negishi 1995; reviewed in Mustelin 2003). Roifman described in 1995 a new type of selective T-cell deficiency characterized by persistent infections reminiscent of severe combined immunodeficiency (Roifman 1995). The patients carry a mutation of ZAP70, resulting in a loss of the kinase activity. The study revealed that ZAP70 kinase appears to be indispensable for the development of CD8 single-positive T cells as well as for the signal transduction and function of single-positive CD4 T cells. However, positive selection of CD4-positive T cells occurs in SCID patients, but the peripheral CD4-T cells do not respond normally to mitogens or to stimulation (Gelfand 1995). The result of ZAP70 mutations in humans leading to SCID have been described in the section above.
Entity Chronic lymphocytic leukemia (CLL)
Note ZAP70 was first thought to be uniquely expressed in T-cells, thymocytes and NK-cells. However, microarray analyses in CLL revealed that some B-cells expressed ZAP70 (Rosenwald 2001). CLL is characterized by a clonal expansion of neoplastic CD19+, CD5+, CD23+ B-cells in the blood, bone marrow, lymph nodes and spleen (Chiorazzi 2005). The heterogenous clinical course identifies two subsets of patients that includes the levels of CD38, the mutational status of immunoglobulin (Ig) heavy chain variable regions (VH) and cytogenetic abnormalities. Indeed, ZAP70 was found to be most discriminating gene between the two subsets of CLL, with higher expression of ZAP70 in the unmutated IgVH CLL group (Rosenwald 2001). Several studies validated this finding and reported that ZAP70 predicted an unfavorable disease course in terms of disease progression and overall survival (Crespo 2003; Orchard 2004; Wiestner 2003; and review in Rodríguez-Vicente 2013; Rosenquist 2013), but discordant results exists (Kröber 2006). It was also shown that ZAP70 is a better predictor of the need for treatment than IgVH status (Rassenti 2004). Chen et al showed early that expression of ZAP70 is associated with increased B-cell receptor signaling in CLL (Chen 2002), but it seems like the presence of ZAP70 in CLL is independent of its kinase activity (Chen 2008), suggesting that the function is more likely as an adaptor molecule to facilitate BCR signaling in CLL, or may compete for a negative regulator of Syk (review in Au-Yeung 2009). Rassenti et al showed in 2008 that ZAP70 levels can be used as an independent marker of clinical outcome in CLL (Rassenti 2008). The clinical course is correlated with augmented signaling down the BCR pathway, albeit not necessarily due to its enzymatic actions (Gobessi 2007; review in Chiorazzi 2012). It was also suggested that ZAP-70 retards internalization of surface membrane IgM and CD79b from the cell membrane, leading to prolonged BCR pathway signaling. An important component of ZAP-70 expression is indeed trafficking to solid tissue niches where signaling through chemokine receptors and BCRs might promote survival and further proliferation (Chiorazzi 2012). Many research groups are now focusing on the microenvironment and, for instance the role of chemokines, in the disease progress of CLL (review in Burger 2014 and Ten hacken 2015). The major CLL compartments in humans are lymph nodes (LN), bone marrow (BM) and peripheral blood (PB), which are, in different ways, giving stimuli to the neoplastic B cells. Different cell types such as stromal cells, nurselike cells and lymphoma associated macrophages will interact in a complex cross-talk with CLL cells, together with T cells and NK cells (Burger 2014). These cells communicate with the CLL cells through an extensive network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors (Ten hacken 2015), resulting in either increased or decreased clonal growth and downstream intracellular signaling.
Entity Non-Hodgkin lymphoma
Note ZAP70 is expressed in malignant non-Hodgkin lymphoma (NHL) B-cell subsets, including precursor B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, multiple myeoloma, Hodgkin lymphoma and more(Sup 2004, Admirand 2004; Wang 2005; Carreras 2005; Scielzo 2006).
Entity B-cell acute lymphoblastic leukemia (B-ALL)
Note ZAP-70 was consistently expressed and phosphorylated on Tyr319 in B-lineage ALL cells (Guillaume 2005). Crespo et al also found an expression of ZAP70 in 56% of B-ALL cases with pro/pre B cell phenotype (Crespo 2006), whereas childhood B-ALL showed even higher expression, in nine out of twelve cases (Wandroo 2008). In adult B-ALL, both less and more frequent ZAP70 expression can be detected (Wang 2005; Chakupurakal 2012).
Entity Diffuse large B-cell lymphoma
Note ZAP70 was expressed in a significantly higher percentage of tumor cells in the clinically more aggressive non-germinal center (GC) group compared with the prognostically favourable GC group (Fridberg 2007).
Entity Hodgkin lymphoma
Note ZAP70 is expressed in rare cases of classic Hodgkin lymphoma (Sup 2004) whereas two other independent studies did not detect any ZAP70-positive cells in Hodgkin lymphoma specimens (Admirand 2004; Carreras 2005).
Entity Anaplastic large cell lymphoma
Note Anaplastic large cell lymphoma (ALCL) is a peripheral T cell lymphoma, often with defective expression of the TCR (Bonzheim 2004). Bonzheim et al showed that ZAP-70 was lacking in more than 70% of all ALCL cases studied. Altogether, the lack of CD3 and ZAP70 contribute to the dysregulation of intracellular signaling pathways controlling T cell activation and survival.
Entity Rheumatoid arthritis
Note B cells play an important role in the pathogenesis of rheumatoid arthritis(RA). It has been shown that ZAP70 expression in synovial fluid B cells obtained from RA patients was increased compared to SF B cells of osteoarthritis patients (Tolusso 2009). Moreover, B cell apoptosis studied in vitro showed that the ZAP70- B cells spontaneously undergoing apoptosis were significantly higher than ZAP70+ B cells. The authors concluded that the presence of ZAP70+ B cells increased survival and local inflammation in RA (Tolusso 2009).


ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain
Chan AC, Iwashima M, Turck CW, Weiss A
Cell 1992 Nov 13;71(4):649-62
PMID 1423621
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
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
PMID 20452964
Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor
Hatada MH, Lu X, Laird ER, Green J, Morgenstern JP, Lou M, Marr CS, Phillips TB, Ram MK, Theriault K, et al
Nature 1995 Sep 7;377(6544):32-8
PMID 7659156
Structural basis for the inhibition of tyrosine kinase activity of ZAP-70
Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J
Cell 2007 May 18;129(4):735-46
PMID 17512407
Intramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases
Brdicka T, Kadlecek TA, Roose JP, Pastuszak AW, Weiss A
Mol Cell Biol 2005 Jun;25(12):4924-33
PMID 15923611
Stability of an autoinhibitory interface in the structure of the tyrosine kinase ZAP-70 impacts T cell receptor response
Deindl S, Kadlecek TA, Cao X, Kuriyan J, Weiss A
Proc Natl Acad Sci U S A 2009 Dec 8;106(49):20699-704
PMID 19920178
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
Functional characterization of a signal transducing motif present in the T cell antigen receptor zeta chain
Irving BA, Chan AC, Weiss A
J Exp Med 1993 Apr 1;177(4):1093-103
PMID 8459204
Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia
Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X, Yang L, Pickeral OK, Rassenti LZ, Powell J, Botstein D, Byrd JC, Grever MR, Cheson BD, Chiorazzi N, Wilson WH, Kipps TJ, Brown PO, Staudt LM
J Exp Med 2001 Dec 3;194(11):1639-47
PMID 11733578
Unexpected requirement for ZAP-70 in pre-B cell development and allelic exclusion
Schweighoffer E, Vanes L, Mathiot A, Nakamura T, Tybulewicz VL
Immunity 2003 Apr;18(4):523-33
PMID 12705855
ZAP-70 is expressed by a subset of normal human B-lymphocytes displaying an activated phenotype
Nolz JC, Tschumper RC, Pittner BT, Darce JR, Kay NE, Jelinek DF
Leukemia 2005 Jun;19(6):1018-24
PMID 15800671
ZAP-70 expression in normal pro/pre B cells, mature B cells, and in B-cell acute lymphoblastic leukemia
Crespo M, Villamor N, Giné E, Muntañola A, Colomer D, Marafioti T, Jones M, Camós M, Campo E, Montserrat E, Bosch F
Clin Cancer Res 2006 Feb 1;12(3 Pt 1):726-34
PMID 16467082
ZAP-70 is expressed by normal and malignant human B-cell subsets of different maturational stage
Scielzo C, Camporeale A, Geuna M, Alessio M, Poggi A, Zocchi MR, Chilosi M, Caligaris-Cappio F, Ghia P
Leukemia 2006 Apr;20(4):689-95
PMID 16482211
Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function
Chan AC, Dalton M, Johnson R, Kong GH, Wang T, Thoma R, Kurosaki T
EMBO J 1995 Jun 1;14(11):2499-508
PMID 7781602
Activating and inhibitory mutations in adjacent tyrosines in the kinase domain of ZAP-70
Wange RL, Guitián R, Isakov N, Watts JD, Aebersold R, Samelson LE
J Biol Chem 1995 Aug 11;270(32):18730-3
PMID 7642520
Binding of ZAP-70 to phosphorylated T-cell receptor zeta and eta enhances its autophosphorylation and generates specific binding sites for SH2 domain-containing proteins
Neumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Shaw AS
Mol Cell Biol 1995 Jun;15(6):3171-8
PMID 7760813
The protein tyrosine kinase ZAP-70 can associate with the SH2 domain of proto-Vav
Katzav S, Sutherland M, Packham G, Yi T, Weiss A
J Biol Chem 1994 Dec 23;269(51):32579-85
PMID 7798261
Activation of p56lck by p72syk through physical association and N-terminal tyrosine phosphorylation
Couture C, Baier G, Oetken C, Williams S, Telford D, Marie-Cardine A, Baier-Bitterlich G, Fischer S, Burn P, Altman A, et al
Mol Cell Biol 1994 Aug;14(8):5249-58
PMID 7518561
p56lck interacts via its src homology 2 domain with the ZAP-70 kinase
Duplay P, Thome M, Hervé F, Acuto O
J Exp Med 1994 Apr 1;179(4):1163-72
PMID 8145035
ZAP70: a master regulator of adaptive immunity
Fischer A, Picard C, Chemin K, Dogniaux S, le Deist F, Hivroz C
Semin Immunopathol 2010 Jun;32(2):107-16
PMID 20135127
SHP2 regulates IL-2 induced MAPK activation, but not Stat3 or Stat5 tyrosine phosphorylation, in cutaneous T cell lymphoma cells
Lundin Brockdorff J, Woetmann A, Mustelin T, Kaltoft K, Zhang Q, Wasik MA, Röpke C, Ødum N
Cytokine 2002 Nov 24;20(4):141-7
PMID 12543077
Analysis of the interaction of ZAP-70 and syk protein-tyrosine kinases with the T-cell antigen receptor by plasmon resonance
Bu JY, Shaw AS, Chan AC
Proc Natl Acad Sci U S A 1995 May 23;92(11):5106-10
PMID 7761456
The structure, regulation, and function of ZAP-70
Au-Yeung BB, Deindl S, Hsu LY, Palacios EH, Levin SE, Kuriyan J, Weiss A
Immunol Rev 2009 Mar;228(1):41-57
PMID 19290920
Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker
Yan Q, Barros T, Visperas PR, Deindl S, Kadlecek TA, Weiss A, Kuriyan J
Mol Cell Biol 2013 Jun;33(11):2188-201
PMID 23530057
Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function
Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, Johnson R, Kong G, Chan AC, Findell PR
J Biol Chem 1996 Aug 16;271(33):19641-4
PMID 8702662
LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation
Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE
Cell 1998 Jan 9;92(1):83-92
PMID 9489702
The Cbl phosphotyrosine-binding domain selects a D(N/D)XpY motif and binds to the Tyr292 negative regulatory phosphorylation site of ZAP-70
Lupher ML Jr, Songyang Z, Shoelson SE, Cantley LC, Band H
J Biol Chem 1997 Dec 26;272(52):33140-4
PMID 9407100
T cell activation stimulates the association of enzymatically active tyrosine-phosphorylated ZAP-70 with the Crk adapter proteins
Gelkop S, Isakov N
J Biol Chem 1999 Jul 30;274(31):21519-27
PMID 10419455
Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling
Di Bartolo V, Mège D, Germain V, Pelosi M, Dufour E, Michel F, Magistrelli G, Isacchi A, Acuto O
J Biol Chem 1999 Mar 5;274(10):6285-94
PMID 10037717
Phosphorylation of Tyr319 in ZAP-70 is required for T-cell antigen receptor-dependent phospholipase C-gamma1 and Ras activation
Williams BL, Irvin BJ, Sutor SL, Chini CC, Yacyshyn E, Bubeck Wardenburg J, Dalton M, Chan AC, Abraham RT
EMBO J 1999 Apr 1;18(7):1832-44
PMID 10202147
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 2002 Jul 5;277(27):24220-4
Tyrosine phosphorylation of VHR phosphatase by ZAP-70
Alonso A, Rahmouni S, Williams S, van Stipdonk M, Jaroszewski L, Godzik A, Abraham RT, Schoenberger SP, Mustelin T
Nat Immunol 2003 Jan;4(1):44-8
PMID 12447358
Redundant role for Zap70 in B cell development and activation
Fallah-Arani F, Schweighoffer E, Vanes L, Tybulewicz VL
Eur J Immunol 2008 Jun;38(6):1721-33
PMID 18465772
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
PMID 18048647
Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis
Taniguchi T, Kobayashi T, Kondo J, Takahashi K, Nakamura H, Suzuki J, Nagai K, Yamada T, Nakamura S, Yamamura H
J Biol Chem 1991 Aug 25;266(24):15790-6
PMID 1874735
Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling
Chan AC, van Oers NS, Tran A, Turka L, Law CL, Ryan JC, Clark EA, Weiss A
J Immunol 1994 May 15;152(10):4758-66
PMID 8176201
Distinct roles for Syk and ZAP-70 during early thymocyte development
Palacios EH, Weiss A
J Exp Med 2007 Jul 9;204(7):1703-15
Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase
Kong GH, Bu JY, Kurosaki T, Shaw AS, Chan AC
Immunity 1995 May;2(5):485-92
PMID 7538440
Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase
Arpaia E, Shahar M, Dadi H, Cohen A, Roifman CM
Cell 1994 Mar 11;76(5):947-58
PMID 8124727
ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency
Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, Iwashima M, Parslow TG, Weiss A
Science 1994 Jun 10;264(5165):1599-601
PMID 8202713
ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency
Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, Iwashima M, Parslow TG, Weiss A
Science 1994 Jun 10;264(5165):1599-601
PMID 8202713
Identification of a novel mutation in ZAP70 and prenatal diagnosis in a Turkish family with severe combined immunodeficiency disorder
Karaca E, Karakoc-Aydiner E, Bayrak OF, Keles S, Sevli S, Barlan IB, Yuksel A, Chatila TA, Ozen M
Gene 2013 Jan 10;512(2):189-93
PMID 23124046
Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of ZAP-70
Elder ME, Skoda-Smith S, Kadlecek TA, Wang F, Wu J, Weiss A
J Immunol 2001 Jan 1;166(1):656-61
PMID 11123350
Temperature-sensitive ZAP70 mutants degrading through a proteasome-independent pathway
Matsuda S, Suzuki-Fujimoto T, Minowa A, Ueno H, Katamura K, Koyasu S
Restoration of a kinase domain mutant by Cdc37 J Biol Chem
PMID 10574909
Alternative antigen receptor (TCR) signaling in T cells derived from ZAP-70-deficient patients expressing high levels of Syk
Noraz N, Schwarz K, Steinberg M, Dardalhon V, Rebouissou C, Hipskind R, Friedrich W, Yssel H, Bacon K, Taylor N
J Biol Chem 2000 May 26;275(21):15832-8
PMID 10748099
Differential requirement of ZAP-70 for CD2-mediated activation pathways of mature human T cells
Meinl E, Lengenfelder D, Blank N, Pirzer R, Barata L, Hivroz C
J Immunol 2000 Oct 1;165(7):3578-83
PMID 11034358
Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency
Turul T, Tezcan I, Artac H, de Bruin-Versteeg S, Barendregt BH, Reisli I, Sanal O, van Dongen JJ, van der Burg M
Eur J Pediatr 2009 Jan;168(1):87-93
Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity
Picard C, Dogniaux S, Chemin K, Maciorowski Z, Lim A, Mazerolles F, Rieux-Laucat F, Stolzenberg MC, Debre M, Magny JP, Le Deist F, Fischer A, Hivroz C
Eur J Immunol 2009 Jul;39(7):1966-76
PMID 19548248
Essential role for ZAP-70 in both positive and negative selection of thymocytes
Negishi I, Motoyama N, Nakayama K, Nakayama K, Senju S, Hatakeyama S, Zhang Q, Chan AC, Loh DY
Nature 1995 Aug 3;376(6539):435-8
PMID 7630421
A mutation in zap-70 protein tyrosine kinase results in a selective immunodeficiency
Roifman CM
J Clin Immunol 1995 Nov;15(6 Suppl):52S-62S
PMID 8613493
Absence of ZAP-70 prevents signaling through the antigen receptor on peripheral blood T cells but not on thymocytes
Gelfand EW, Weinberg K, Mazer BD, Kadlecek TA, Weiss A
J Exp Med 1995 Oct 1;182(4):1057-65
PMID 7561679
Chronic lymphocytic leukemia
Chiorazzi N, Rai KR, Ferrarini M
N Engl J Med 2005 Feb 24;352(8):804-15
PMID 15728813
ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia
Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marcé S, López-Guillermo A, Campo E, Montserrat E
N Engl J Med 2003 May 1;348(18):1764-75
PMID 12724482
ZAP-70 expression and prognosis in chronic lymphocytic leukaemia
Orchard JA, Ibbotson RE, Davis Z, Wiestner A, Rosenwald A, Thomas PW, Hamblin TJ, Staudt LM, Oscier DG
Lancet 2004 Jan 10;363(9403):105-11
PMID 14726163
ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile
Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE, Zhao H, Ibbotson RE, Orchard JA, Davis Z, Stetler-Stevenson M, Raffeld M, Arthur DC, Marti GE, Wilson WH, Hamblin TJ, Oscier DG, Staudt LM
Blood 2003 Jun 15;101(12):4944-51
PMID 12595313
Chronic lymphocytic leukemia: a clinical and molecular heterogenous disease
Rodríguez-Vicente AE, Díaz MG, Hernández-Rivas JM
Cancer Genet 2013 Mar;206(3):49-62
PMID 23531595
Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand? Leuk Lymphoma
Rosenquist R, Cortese D, Bhoi S, Mansouri L, Gunnarsson R
2013 Nov;54(11):2351-64 doi: 10
PMID 23480493
Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia
Kröber A, Bloehdorn J, Hafner S, Bühler A, Seiler T, Kienle D, Winkler D, Bangerter M, Schlenk RF, Benner A, Lichter P, Döhner H, Stilgenbauer S
J Clin Oncol 2006 Feb 20;24(6):969-75
PMID 16418492
ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia
Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG, Neuberg DS, Flinn IW, Rai KR, Byrd JC, Kay NE, Greaves A, Weiss A, Kipps TJ
N Engl J Med 2004 Aug 26;351(9):893-901
PMID 15329427
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
PMID 12393534
Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia
Rassenti LZ, Jain S, Keating MJ, Wierda WG, Grever MR, Byrd JC, Kay NE, Brown JR, Gribben JG, Neuberg DS, He F, Greaves AW, Rai KR, Kipps TJ
Blood 2008 Sep 1;112(5):1923-30
PMID 18577710
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
PMID 17038529
Implications of new prognostic markers in chronic lymphocytic leukemia
Chiorazzi N
Hematology Am Soc Hematol Educ Program 2012;2012:76-87
PMID 23233564
The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies
Burger JA, Gribben JG
Semin Cancer Biol 2014 Feb;24:71-81
PMID 24018164
Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment
Ten Hacken E, Burger JA
Biochim Biophys Acta 2015 Jul 17
PMID 26193078
ZAP-70 expression in B-cell hematologic malignancy is not limited to CLL/SLL
Sup SJ, Domiati-Saad R, Kelley TW, Steinle R, Zhao X, Hsi ED
Am J Clin Pathol 2004 Oct;122(4):582-7
PMID 15487457
Immunohistochemical detection of ZAP-70 in 341 cases of non-Hodgkin and Hodgkin lymphoma
Admirand JH, Rassidakis GZ, Abruzzo LV, Valbuena JR, Jones D, Medeiros LJ
Mod Pathol 2004 Aug;17(8):954-61
PMID 15133473
Distribution and ZAP-70 expression of WHO lymphoma categories in Shanxi, China: a review of 447 cases using a tissue microarray technique
Wang J, Young L, Win W, Taylor CR
Appl Immunohistochem Mol Morphol 2005 Dec;13(4):323-32
PMID 16280661
Immunohistochemical analysis of ZAP-70 expression in B-cell lymphoid neoplasms
Carreras J, Villamor N, Colomo L, Moreno C, Ramón y Cajal S, Crespo M, Tort F, Bosch F, López-Guillermo A, Colomer D, Montserrat E, Campo E
J Pathol 2005 Mar;205(4):507-13
PMID 15685592
ZAP-70 tyrosine kinase is constitutively expressed and phosphorylated in B-lineage acute lymphoblastic leukemia cells
Guillaume N, Alleaume C, Munfus D, Capiod JC, Touati G, Pautard B, Desablens B, Lefrère JJ, Gouilleux F, Lassoued K, Gouilleux-Gruart V
Haematologica 2005 Jul;90(7):899-905
PMID 15996927
ZAP-70 is highly expressed in most cases of childhood pre-B cell acute lymphoblastic leukemia
Wandroo F, Bell A, Darbyshire P, Pratt G, Stankovic T, Gordon J, Lawson S, Moss P
Int J Lab Hematol 2008 Apr;30(2):149-57
PMID 18333847
Analysis of ZAP70 expression in adult acute lymphoblastic leukaemia by real time quantitative PCR
Chakupurakal G, Bell A, Griffiths M, Wandroo F, Moss P
Mol Cytogenet 2012 May 1;5(1):22
PMID 22548957
Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma: higher expression of ZAP70 and PKC-beta II in the non-germinal center group and poor survival in patients deficient in nuclear PTEN
Fridberg M, Servin A, Anagnostaki L, Linderoth J, Berglund M, Söderberg O, Enblad G, Rosén A, Mustelin T, Jerkeman M, Persson JL, Wingren AG
Leuk Lymphoma 2007 Nov;48(11):2221-32
PMID 17926183
Anaplastic large cell lymphomas lack the expression of T-cell receptor molecules or molecules of proximal T-cell receptor signaling
Bonzheim I, Geissinger E, Roth S, Zettl A, Marx A, Rosenwald A, Müller-Hermelink HK, Rüdiger T
Blood 2004 Nov 15;104(10):3358-60
PMID 15297316
Synovial B cells of rheumatoid arthritis express ZAP-70 which increases the survival and correlates with the inflammatory and autoimmune phenotype
Tolusso B, De Santis M, Bosello S, Gremese E, Gobessi S, Cuoghi I, Totaro MC, Bigotti G, Rumi C, Efremov DG, Ferraccioli G
Clin Immunol 2009 Apr;131(1):98-108
PMID 19136305


This paper should be referenced as such :
Delfani P, El-Schich Z, Gjörloff Wingren A
ZAP70 (zeta-chain (TCR) associated protein kinase 70kDa);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas)
  t(2;14)(p13-16;q32) IGH/BCL11A
t(5;9)(q33;q22) ITK/SYK

External links

HGNC (Hugo)ZAP70   12858
Entrez_Gene (NCBI)ZAP70  7535  zeta-chain (TCR) associated protein kinase 70kDa
GeneCards (Weizmann)ZAP70
Ensembl hg19 (Hinxton)ENSG00000115085 [Gene_View]  chr2:98330031-98356323 [Contig_View]  ZAP70 [Vega]
Ensembl hg38 (Hinxton)ENSG00000115085 [Gene_View]  chr2:98330031-98356323 [Contig_View]  ZAP70 [Vega]
ICGC DataPortalENSG00000115085
TCGA cBioPortalZAP70
AceView (NCBI)ZAP70
Genatlas (Paris)ZAP70
SOURCE (Princeton)ZAP70
Genomic and cartography
GoldenPath hg19 (UCSC)ZAP70  -     chr2:98330031-98356323 +  2q12   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)ZAP70  -     2q12   [Description]    (hg38-Dec_2013)
EnsemblZAP70 - 2q12 [CytoView hg19]  ZAP70 - 2q12 [CytoView hg38]
Mapping of homologs : NCBIZAP70 [Mapview hg19]  ZAP70 [Mapview hg38]
OMIM176947   269840   
Gene and transcription
Genbank (Entrez)AB083211 AK303341 AK310628 AK310637 AL832287
RefSeq transcript (Entrez)NM_001079 NM_207519
RefSeq genomic (Entrez)NC_000002 NC_018913 NG_007727 NT_005403 NW_004929303
Consensus coding sequences : CCDS (NCBI)ZAP70
Cluster EST : UnigeneHs.234569 [ NCBI ]
CGAP (NCI)Hs.234569
Alternative Splicing : Fast-db (Paris)GSHG0016697
Alternative Splicing GalleryENSG00000115085
Gene ExpressionZAP70 [ NCBI-GEO ]     ZAP70 [ SEEK ]   ZAP70 [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP43403 (Uniprot)
NextProtP43403  [Medical]  [Publications]
With graphics : InterProP43403
Splice isoforms : SwissVarP43403 (Swissvar)
Catalytic activity : Enzyme2.7.10.2 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)    SH2 (PS50001)   
Domains : Interpro (EBI)Kinase-like_dom    Kinase_SYK/ZAP-70_inter-SH2    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser-Thr/Tyr_kinase_cat_dom    SH2    Tyr_kinase_AS    Tyr_kinase_cat_dom    Tyr_kinase_non-rcpt_SYK/ZAP70   
Related proteins : CluSTrP43403
Domain families : Pfam (Sanger)Pkinase_Tyr (PF07714)    SH2 (PF00017)   
Domain families : Pfam (NCBI)pfam07714    pfam00017   
Domain families : Smart (EMBL)SH2 (SM00252)  TyrKc (SM00219)  
DMDM Disease mutations7535
Blocks (Seattle)P43403
PDB (SRS)1FBV    1M61    1U59    2CBL    2OQ1    2OZO    2Y1N    3ZNI    4A4B    4A4C    4K2R   
PDB (PDBSum)1FBV    1M61    1U59    2CBL    2OQ1    2OZO    2Y1N    3ZNI    4A4B    4A4C    4K2R   
PDB (IMB)1FBV    1M61    1U59    2CBL    2OQ1    2OZO    2Y1N    3ZNI    4A4B    4A4C    4K2R   
PDB (RSDB)1FBV    1M61    1U59    2CBL    2OQ1    2OZO    2Y1N    3ZNI    4A4B    4A4C    4K2R   
Human Protein AtlasENSG00000115085
Peptide AtlasP43403
IPIIPI00329789   IPI00410185   IPI00885038   
Protein Interaction databases
IntAct (EBI)P43403
Ontologies - Pathways
Ontology : AmiGOimmunological synapse  phosphotyrosine binding  adaptive immune response  protein tyrosine kinase activity  protein tyrosine kinase activity  protein tyrosine kinase activity  non-membrane spanning protein tyrosine kinase activity  receptor binding  protein binding  ATP binding  cytoplasm  cytosol  plasma membrane  plasma membrane  cell-cell junction  protein phosphorylation  protein phosphorylation  immune response  transmembrane receptor protein tyrosine kinase signaling pathway  peptidyl-tyrosine phosphorylation  peptidyl-tyrosine phosphorylation  cell differentiation  T cell differentiation  extrinsic component of cytoplasmic side of plasma membrane  intracellular signal transduction  peptidyl-tyrosine autophosphorylation  T cell receptor complex  T cell activation  B cell activation  beta selection  positive thymic T cell selection  negative thymic T cell selection  innate immune response  membrane raft  positive regulation of T cell differentiation  positive regulation of alpha-beta T cell differentiation  positive regulation of alpha-beta T cell proliferation  positive regulation of calcium-mediated signaling  T cell receptor signaling pathway  T cell aggregation  T cell migration  
Ontology : EGO-EBIimmunological synapse  phosphotyrosine binding  adaptive immune response  protein tyrosine kinase activity  protein tyrosine kinase activity  protein tyrosine kinase activity  non-membrane spanning protein tyrosine kinase activity  receptor binding  protein binding  ATP binding  cytoplasm  cytosol  plasma membrane  plasma membrane  cell-cell junction  protein phosphorylation  protein phosphorylation  immune response  transmembrane receptor protein tyrosine kinase signaling pathway  peptidyl-tyrosine phosphorylation  peptidyl-tyrosine phosphorylation  cell differentiation  T cell differentiation  extrinsic component of cytoplasmic side of plasma membrane  intracellular signal transduction  peptidyl-tyrosine autophosphorylation  T cell receptor complex  T cell activation  B cell activation  beta selection  positive thymic T cell selection  negative thymic T cell selection  innate immune response  membrane raft  positive regulation of T cell differentiation  positive regulation of alpha-beta T cell differentiation  positive regulation of alpha-beta T cell proliferation  positive regulation of calcium-mediated signaling  T cell receptor signaling pathway  T cell aggregation  T cell migration  
Pathways : BIOCARTAActivation of Csk by cAMP-dependent Protein Kinase Inhibits Signaling through the T Cell Receptor [Genes]    T Cell Receptor Signaling Pathway [Genes]    Lck and Fyn tyrosine kinases in initiation of TCR Activation [Genes]   
Pathways : KEGGRas signaling pathway    NF-kappa B signaling pathway    Natural killer cell mediated cytotoxicity    T cell receptor signaling pathway    Primary immunodeficiency   
REACTOMEP43403 [protein]
REACTOME PathwaysREACT_6900 Immune System [pathway]
Protein Interaction DatabaseZAP70
Atlas of Cancer Signalling NetworkZAP70
Wikipedia pathwaysZAP70
Gene fusions - Rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerZAP70 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ZAP70
Exome Variant ServerZAP70
SNP (GeneSNP Utah)ZAP70
Genetic variants : HAPMAPZAP70
Genomic Variants (DGV)ZAP70 [DGVbeta]
ICGC Data PortalZAP70 
TCGA Data PortalZAP70 
Tumor PortalZAP70
Somatic Mutations in Cancer : COSMICZAP70 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
DoCM (Curated mutations) ZAP70
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
DECIPHER (Syndromes)2:98330031-98356323
CONAN: Copy Number AnalysisZAP70 
Mutations and Diseases : HGMDZAP70
OMIM176947    269840   
NextProtP43403 [Medical]
Disease Genetic AssociationZAP70
Huge Navigator ZAP70 [HugePedia]  ZAP70 [HugeCancerGEM]
snp3D : Map Gene to Disease7535
DGIdb (Drug Gene Interaction db)ZAP70
BioCentury BCIQZAP70
General knowledge
Homologs : HomoloGeneZAP70
Homology/Alignments : Family Browser (UCSC)ZAP70
Phylogenetic Trees/Animal Genes : TreeFamZAP70
Chemical/Protein Interactions : CTD7535
Chemical/Pharm GKB GenePA37447
Clinical trialZAP70
Cancer Resource (Charite)ENSG00000115085
Other databases
PubMed284 Pubmed reference(s) in Entrez
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Nov 24 19:00:43 CET 2015

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us