Phosphotyrosine Antibody Review and FAQs
Mary Johnson (mary at labome dot com)
Synatom Research, Princeton, New Jersey, United States
DOI
http://dx.doi.org/10.13070/mm.en.3.173
Date
last modified : 2014-08-23; original version : 2013-02-15
Cite as
MATER METHODS 2013;3:173
Abstract

A comprehensive review of phosphotyrosine antibodies, FAQs and purchase guide.

Phosphotyrosine antibody

This is a review about phosphotyrosine antibodies (phospho-tyrosine antibodies), based on 82 published articles as of August 23, 2014, using phosphotyrosine antibodies in western blot, immunoprecipitation, immunocytochemistry, and other immunological technologies in randomly selected publications that Labome has been surveying systematically since 2006. This review is aimed to facilitate the identification of the best-suited phosphotyrosine antibodies. Phosphotyrosine antibodies can be obtained from many suppliers. The article also addresses some of commonly asked questions about phosphotyrosine antibodies.

Phosphotyrosine Antibody Review and FAQs figure 1
Figure 1. An example of phosphorylation studies before the usage of anti-phosphotyrosine antibodies (from [1] ).

Tyrosine phosphorylation is one of the major means of cell signaling transduction and enzymatic activity regulation. The advent of anti-phosphotyrosine antibodies is a significant event in signal transduction research. Before the availability of anti-phosphotyrosine antibodies, tyrosyl phosphorylation of proteins and enzymes was investigated through hazardous and time-consuming radioactive experiments [1] ; Figure 1 examplifies such an experiment. Anti-phosphotyrosine antibodies are commonly used in western blots after a targeted protein has been immunoprecipitated to measure the tyrosyl phosphorylation of the protein. They are also used on cell lysates to examine the overall change of tyrosine phosphorylation level in response to various treatments.

Review of other general (nongene-specific) antibodies are available: tag antibodies ( HA, c-Myc and His6); western blot loading controls ( beta actin, alpha tubulin); secondary antibodies.

Phosphotyrosine Antibody Review and FAQs figure 2
Figure 2. A composite figure derived from [2] indicating the substrate selectivity of various anti-phosphotyrosine antibodies. Upper table: sources and related information about the seven anti-phosphotyrosine antibodies. Middle panel left figure: substrate selectivity of anti-phosphotyrosine antibodies in dot blots against synthetic phosphotyrosine peptides. Middle panel right figure: variations in bands and intensities of anti-phosphotyrosine antibodies in western blots against the equally-loaded samples. Bottom table: summary of substrate selectivity against phosphopeptides and phosphorylated CagA proteins by commercial α-phosphotyrosine antibodies.
Phosphotyrosine antibody clones

Three clones are commonly used: 4G10, PY20, and p-TYR-100. PY20 clone of IgG2b isotype was first developed and described by Dr. John R. Glenney, Jr and his colleagues in 1988 [3]. The other two clones were developed by commerical identities (Upstate/EMD Millipore 4G10 and New England Biolab/Cell Signaling Technology p-TYR-100).

Anti-phosphotyrosine antibodies binding to tyrosine-phosphorylated peptides exhibit substantial sequence selectivity. Michele Tinti et al. demonstrated that different phosphotyrosine antibody clones recognized their target sites in a sequence-specific manner and that this recognition differed from each other [4]. According to peptide microarray data, although different clones (i.e. 4G10, pY20 and p-TYR-100) showed a common enrichment of prolines at position +3 and leucine at position -1 with respect to the phosphorylated tyrosine in the peptides, differences between the sequence preferences were observed. For example, clone 4G10 displayed a sequence context preference for Pro, Thr, Val and Phe at position -3. Both 4G10 and p-TYR-100 bindings were likely to be hindered by a negative charge at position -1, while pY20 was more sensitive to a positive charge at the same position. Among phosphotyrosine peptides, a total of 10%-20% could be uniquely recognized by one antibody. These specificity differences were reflected in Western blots, where band intensities of 4G10 and p-TYR-100 differed and pY20 even stained an additional group of 95–34 kDa proteins [4]. This substantial sequence selectivity is further evidenced by a direct comparison of seven commercial antibodies with regards to synthetic phospho-peptides in dot blots and phosphorylated CagA protein in Western blots (Figure 2) [2].

SupplierNum
Upstate Biotechnology / EMD Millipore45
Santa Cruz Biotechnology15
BD Transduction Laboratories14
Cell Signaling Technology6
UBI3
ICN Biomedicals2
Sigma2
Molecular Probes / Invitrogen / LifeTech / Thermo Fisher1
Amersham Biosciences1
Biomol/Enzo Life Sciences1
Table 1. Major suppliers of phosphotyrosine antibodies and the numbers of citations among the 82 publications surveyed by Labome.
Phosphotyrosine antibody in literature

Table 1 lists the suppliers of phosphotyrosine antibodies among the 82 publications surveyed by Labome. Among the 23 articles that indicated clone names, 18 articles listed 4G10, and 6 articles listed PY20 clone (one article listed both clones [5] ). Table 2 lists the major applications of phosphotyrosine antibodies among the publications.

ApplicationnumTop suppliers
western blot64Upstate Biotechnology/EMD Millipore, BD Transduction Laboratories, Santa Cruz
immunoprecipitation16Upstate/EMD Millipore, Santa Cruz Biotechnology, BD Transduction Laboratories
immunocytochemistry6Upstate Biotechnology/EMD Millipore
immunohistochemistry2
Table 2. Applications of phosphotyrosine antibodies and their numbers of citations among the 82 publications surveyed by Labome.
Upstate Biotechnology/EMD Millipore

Upstate Biotechnology is now part of EMD Millipore. Upstate Biotechnology has provided some of most commonly used anti-phospho-tyrosine antibodies, including the most commonly used clone 4G10. More than half of the publications cited Upstate anti-phospho-tyrosine antibodies in western blot, immunoprecipitation, and immunocytochemistry.

Upstate anti-phosphotyrosine antibody was used to perform western blot and immunohistochemistry in order to study the function of sema3E-plexin D1 [6], to perform immunoprecipitation in order to study the roles of LRP1 in the adult CNS [7], and western blot analysis (clone 4G10) in order to determine the receptor property of erythropoietin receptor during receptor signaling activation [8] and to study the effect of the facilitation of AMPA receptor synaptic delivery on cognitive enhancement [9]. Among papers published earlier in 2001, K Aoyama used 4G10 in western blot to study a novel dual specificity phosphatase, LMW-DSP2; K Sauer et al used 4G10 in western blot to examine the interaction of HPK1 with BLNK in B cells and with SLP-76 in T cells, A E Aplin et al used 4G10 in western blot to study the regulation of ERK nuclear translocation and Elk-1 phosphorylation by integrin-mediated adhesion; H Konishi et al used it in western blot to study the tyrosine phosphorylation sites of PKC delta in the H2O2-treated cells; C C Chen used both clone PY-20 and clone 4G10 in western blot and immunocytochemistry to study the induction of adhesive signaling in primary human skin fibroblasts; C Gilbert used 4G10 in immunoprecipitation to evaluate the SAM68 roles in signal transduction during human neutrophil phagocytosis. In 2002, clone 4G10 was used in western blots by Matthew N Poy to study the mitogenic action of insulin regulated by Shc and CEACAM1 interaction, by Kenneth L Byron to examine vasopressin signal transduction in A7r5 vascular smooth muscle cells, by Diane Lejeune et al to study STAT3 serine phosphorylation, and in immunocytochemistry by Ann L Moor to localize tyrosine-phosphorylated PLC (pY-PLC) in HTC cells. In 2003, Yosuke Minami et al conducted western blot experiments with Upstate Biotechnology antiphosphotyrosine antibody to differentiate the antiapoptotic pathways between wild-type and mutated FLT3; K C Leung et al used 4G10 in western blot to study the inhibiting effects of estrogen on transcriptional action of GH through the SOCS-2 mediated JAK/STAT pathway; John H Griffin used 4G10 in western blot to study a fusion kinase in EOL-1 cells and the idiopathic hypereosinophilic syndrome. Matthew L Jones in 2004 used 4G10 to immunoprecipitate phosphorylated SHP-1 proteins; Tod A Brown used anti-phosphotyrosine monoclonal antibody in western blot to elucidate the tyrosine phosphorylation of a novel membrane glycoprotein p80/gp140/CUB domain-containing protein 1 in epithelia; Charng-Jui Chen et al used 4G10 in western blot and immunocytochemistry to investigate the inhibition of IL-2 production and proliferation in human T cells by carcinoembryonic antigen-related cellular adhesion molecule 1. In 2005, Upstate Biotechnology anti-phosphotyrosine antibodies were used in western blots to examine the Rac-MKK3/6-p38 pathway in breast epithelial cells by Ilchung Chin, the regulation of the endothelial cell response to Ang-1 through stable interaction between alpha5beta1 integrin and Tie2 tyrosine kinase receptor by Ilaria Cascone et al, the direct interaction between human CNK1 and Raf-1 by Algirdas Ziogas et al, and T-cell receptor-induced activation of phospholipase C-gamma1 by a sequence-independent function of the P-I region of SLP-76 by Ronnie Gonen et al. Upstate Biotech anti-phosphotyrosine antibody was used in immunoprecipitation to study the phosphoproteome analysis of HeLa cells using stable isotope labeling with amino acids in cell culture by Dr. Amanchy in 2005. Upstate Biotechnology anti-phosphotyrosine (1:3000) was used in western blot to demonstrate that lipid rafts sequester Ret away from the degradation machinery to sustain Ret signaling by Dr. Pierchala in 2006. Upstate/Millipore 4G10 antibody was used in western blot to study the role of MNAR in 17beta-estradiol (E2)-induced activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by Dr.Greger in 2007. Additional citations include [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [8] [20] [21] [22] [9] [23] [24] [25] [26] [27] [5] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [7] [45] [6] [43].

Santa Cruz Biotechnology

Among the publications [46] [47] [48] [49] [50] [51] [52] [53] [54] [32] [31] [55], Santa Cruz antiphosphotyrosine (anti-pTyr) antibody was used in western blots to study the downregulation of the Ras-mitogen-activated protein kinase pathway by S Elowe in 2001, and to study the role of beta-arrestin in ubiquitination and IGF-1 receptor down-regulation by Leonard Girnita in 2005; its PY20 anti-phosphotyrosine antibody was used in immunoprecipitation to study the IL-2 production and proliferation in human T cells inhibited by the cell-cell adhesion molecule carcinoembryonic antigen-related cellular adhesion molecule 1 by Charng-Jui Chen 2004; Matthew N Poy in 2002 also used anti-phosphotyrosine antibody (PY20) in immunoprecipitation to study the regulation of insulin mitogenic action by Shc and CEACAM1 interaction, and Santa Cruz Biotechnology phosphotyrosine antibody was used in western blot to investigated the mechanism and function of ubiquitination of protease-activated receptor 2 (PAR2) by Dr. Jacob in 2005. Santa Cruz Biotechnology mouse monoclonal anti-phosphotyrosine antibody was used to perform western blot to investigate the roles of Vav2 and Vav3 in skin cancer [56].

Transduction Laboratories/BD Biosciences

Publications citing BD Biosciences anti-phosphotyrosine antibodies include [57] [58] [59] [60] [61] [11] [62] [63] [64] [65] [66] [29], where Koichi Seta in 2003 used BD Biosciences horseradish peroxidase-conjugated anti-phosphotyrosine monoclonal antibody (RC20H) in western blot to study the angiotensin II-induced trans-activation of the EGF receptor and found that the transactivation was mediated by phosphorylation of tyrosine 319 of the angiotensin II type 1 receptor; the same clone was used by C Sweeney in 2001 in western blot to examine ErbB receptor-mediated signaling pathway stimulation and gene expression; Wen Hong Shen et al in 2004 used a different mouse anti-phosphotyrosine clone (PY20) in both western blot and immunoprecipitation to study cyclin A expression and retinoblastoma hyperphosphorylation; polyclonal anti-phosphotyrosine antibody was used in immunoprecipitation to study vasopressin-induced signal transduction in A7r5 vascular smooth muscle cells by Kenneth L Byron in 2002; and peroxidase-conjugated anti-phosphotyrosine antibody was used in western blots to exploit EphA2 as a therapeutic target of cancer by Dr. Koolpe in 2002.

Cell Signaling Technology

Cell Signaling Technology phosphotyrosine antibody was used in western blot and immunoprecipitation to study the role of p68 RNA helicase [67], in western blot to study cell adhesion molecule [68] and vIL-6 18987143] and its monoclonal mouse anti-phosphotyrosine antibody was used in immunocytochemistry to study supervillin [69].

ICN Biomedicals/MPBIO

ICN Biomedicals monoclonal anti-phosphotyrosine antibody PY20 in western blot to study the involvement of tumor necrosis factor receptor-associated protein 1 (TRAP1) in beta-hydroxyisovalerylshikon-induced apoptosis [70] and the role of aldose reductase pathway during myocardial ischemic injury [71].

Sigma

In 2001, L You used Sigma monoclonal phosphotyrosine antibody in western blot to study migration and signal transduction induced by cell-derived neurotrophic factor (GDNF) in corneal epithelial cells [72].

Amersham Biosciences/GE Health Science

Amersham Biosciences monoclonal anti-phosphotyrosine horseradish peroxidase-conjugated antibody was used in western blot to study insulin receptor catalytic activity inhibition by in 2002 [73].

Commonly asked questions about phosphotyrosine antibodies.

Some of the commonly asked questions are answered here.

How to detect tyrosine phosphorylation of a specific protein?

There are several ways.

  1. use a phosphorylation-specific antibody against the specific protein.
  2. use an antibody against the specific protein to immunoprecipitate both phosphorylated or non-phosphorylated forms of the specific protein, then detect with phosphotyrosine antibodies in Western blot.
  3. use phosphotyrosine antibodies to immunoprecipitate all tyrosine-phosphorylated proteins, and then detect with an antibody against the specific protein.
  4. mass spec.

For detailed discussion of the detection of protein phosphorylation, see Labome article about Protein Modification Research Methods.

During Western blotting of phosphotyrosine antibodies, should nonfat dry milk or BSA be used as the blocking agent?

BSA should be used, since nonfat dry milk contains proteins that are phosphorylated at tyrosine residues.

How long can the lysate samples be stored before detection of tyrosine phosphorylation?

The samples should generally be used fresh, since the proteins might be degraded, and dephosphorylation may occur due to phosphatases.

Is there any anti-phosphotyrosine anybody that can be used to neutralize or block the activities of protein kinases or phosphatases?

We do not know the answer to this question. Anti-phosphotyrosine anybodies have been used for Western blot, immunoprecipitation, immunocytochemistry, and immunohistochemistry.

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