Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_309


Historical Background

The Src homology region 2 (SH) domain-containing protein tyrosine phosphatase-1 (SHP-1) is a member of the large family of protein tyrosine phosphatase (PTP). SHP-1 was identified in hematopoietic cells and organs involved in immune responses such as the spleen, thymus, lymph node, and bone marrow. SHP-1 is also known as hematopoietic cell phosphatase (HCP) because of its expression in these cells. Herein the nomenclature SHP-1 will be used. Back to the beginning of the 1990s, the study of tyrosine kinases was very well advanced; however, knowledge about their natural counterpart the tyrosine phosphatases was still greatly unraveled. Early on, different research groups isolated and identified a protein that contains two SH2 domains with phosphotyrosine phosphatase activity. Soon after, the PTPN6 gene that encodes SHP-1 was mapped to chromosomes 6 and 12 of mouse and human, respectively. Chromosome 6 (and its homologue in human chromosome 12) was also correlated with the autosomal recessive motheaten (“me”) phenotype that affects mice to develop a severe combined immunodeficiency and systemic autoimmunity (Tsui et al. 2006). In line with those findings, the involvement of SHP-1 in diseases was earliest described 15 years before its discovery. The first study to report the motheaten mice was done by Green and Shultz (Green and Shultz 1975), in which they described a recessive mutation in C57Bl/6 mice in the Jackson Laboratory. Those “me” mice exhibit a motheaten phenotype, consisting of disseminated fur-free patches. In addition, these mice developed skin lesion as early as 3 weeks after birth, which progress rapidly, and the mice did not survive over 8 weeks (Green and Shultz 1975). Subsequently, a similar mutation in the PTPN6 loci was described, called viable motheaten (“mev”) as mice can survive longer than “me” mice, up to 9–12 weeks. This mutation, different of “me” (that does not express SHP-1), provides a protein with small deletion or insertion in the PTP domain which results in around 20% of the phosphatase activity of the cells expressing wild type SHP-1 (Kozlowski et al. 1993). Both “me” and “mev” mice develop an unusual pneumonia with a progressive infiltration of macrophages, neutrophils and lymphocytes, as well as spontaneous inflammatory disorder in many organs such as kidney and joints (Zhu et al. 2010). Of interest, peripheral blood monocytes and macrophages from patients with multiple sclerosis expressed less SHP-1 and high levels of demyelination-correlated inflammatory molecules (Christophi et al. 2009).

CRE-LOX recombination system improved SHP-1’s research as it provides a site-specific modification on SHP-1 protein. Conditional deletion of SHP-1 in neutrophils and dendritic cells made possible to discriminate its role in the inflammation and autoimmune diseases, respectively (Abram et al. 2013). Mice with a specific deletion of SHP-1 in neutrophils did not develop autoimmune diseases, but developed a paw inflammation with similar histology to that “me” mice. In contrast, conditional deletion of SHP-1 in dendritic cells caused a splenomegaly, lymphadenopathy, and antinuclear antibody, but not inflammation in the paw of SHP-1-deficient mice (Abram et al. 2013). Autoimmune phenotype is also dependent on the B cells as the conditional deletion of SHP-1 in B cells lead to an increased level of anti-DNA antibody and immune complex-mediated glomerulonephritis (Pao et al. 2007). Thus, these recent studies improve our knowledge concerning the autonomous role of cells from the innate and the adaptive immunity on the previously described “me” phenotype.

PTPN6 Gene, SHP-1 Protein Expression and Structure

Human PTPN6 gene consists of 17 exons, approximately 17 kb in length, leading to the formation of transcripts of 2.4–2.6 kb. The gene has two promoter regions (within exon 1 and 2) hence encodes two forms of proteins that do not show significant difference in their phosphatase activity (Fig. 1).
PTPN6, Fig. 1

Schematic diagram of PTPN6 gene and mutation of murine SHP-1. The schematic representation of PTPN6 gene shows introns in gray and exons in black. Exons which are responsible for encoding the N-terminus SH2 (3, 4), C-terminus SH2 (5, 6), and catalytic (8–14) domains are also shown in numbers. The bottom part represents the promoter regions 1 and 2 that encode slightly different SHP-1 proteins with comparable activity. The upper part denotes the feature of motheaten and viable motheaten mutations. The first phenotype, caused by the motheaten mutation, is generated by deletion of the C at position 288 that creates a cryptic 5’ splice site consensus. Once activated, the mutation leads to the deletion of 101 bp that creates a frame shift, and the stop codon occurs 81 bp downstream of the deleted fragment. The second phenotype, caused by the viable motheaten mutation, occurs due to the substitution of T with A in the phosphatase domain. This mutation disrupts a GT dinucleotides creating two cryptic 5’ splice site – one 15 bp before and the other 69 bp after the normal donor splice site – generating a short (less five amino acids) and a long SHP-1 (with 23 amino acids or more), respectively. For further review, see Wu et al. (2003) and Tsui et al. (2006)

However, there are differences in the initial sequence of the protein and in SHP-1 tissue expression. Promoter 1 (located 7 kb before promoter 2) encodes MLSRG (Methionine-Leucine-Serine-Arginine-Glycine) amino acid sequence in the N-terminal of the form 1 of SHP-1 – (I)SHP-1 – and promoter 2 MVR (Methionine-Valine-Arginine) in the form 2 of SHP-1 – (II)SHP-1. The promoter 1 has two E-box (regulated by USF1 and/or 2), a NF-κB and SP1 binding site as well as a TATA box. The promoter 2 has two GATA sequences, a CCAAT box, a TATA box, and an AP2- and SP1- binding sites. The first promoter is active in nonhematopoietic tissue and the second in the hematopoietic cells. Therefore, (I)SHP-1 is expressed in human epithelial cells and can be induced by PMA via NF-κB activation and (II)SHP-1 in cells related with the immune system such as macrophages, neutrophills, mast cells, lymphocytes, and so on (Wu et al. 2003; Tsui et al. 2006). In addition to immune cells, it was shown that SHP-1 is expressed in hepatocytes and myocytes (Dubois et al. 2006). However, in some epithelial cancer cells both promoters might be used and generate truncated transcripts of SHP-1 lacking exon 3, or both exons 3 and 4. Concerning its cellular localization, (I)SHP-1 is located within the nuclear compartment and the (II)SHP-1 in the cytoplasm of resting cells, suggesting that the two forms of SHP-1 might have different targets (Poole and Jones 2005). The other exons of PTPN6 are responsible for encoding different domains of the protein; hence exons 3 and 4 encode the N-terminal SH2 domain, exons 5 and 6 the C-terminal SH2 domain, and exons 8–10 the catalytic domain (Fig. 2).
PTPN6, Fig. 2

Mechanism of SHP-1 activation. Left panel shows SHP-1 in its “closed” form in steady state (resting) cells. The C-SH2 domain acts as an antenna to search for phosphorylated tyrosil residues and the N-SH2 domain interacts with the catalytic domain (PTP) preventing its activity. The C-terminus of SHP-1 consists of two tyrosine (Y) residues and one serine (S) residue, which positively or negatively regulate the SHP-1 activity. Once cells are activated (right panel), a receptor tyrosine kinase (RTK), inhibitory receptor (IR), or scaffolding adapters become phosphorylated in their tyrosine residues (pY). The C-SH2 domain then binds to pY, changing the conformation of the protein and freeing the catalytic domain to act in to the substrate. For further review, see Pao et al. (2007) and Poole and Jones (2005)

Structurally the SHP-1 protein, similarly to SHP-2, is constituted by two SH2 domains in the N-terminal region (N-SH2 and C-SH2), followed by a classical catalytic PTP domain and the C-terminal region containing two tyrosil (Y536 and Y564) and one serine (S591) phosphorylation sites (Fig. 2). In addition, in the latter region, SHP-1 has a phosphatidic acid binding active site, a functional nuclear localization signal (NLS), and a potential lipid raft-targeting motif (Poole and Jones 2005; Pao et al. 2007). Furthermore, the C-terminal region of SHP-1 can be longer in the SHP-1 L (long form of SHP-1), having 66 amino acids more than SHP-1, due to an alternative splicing (Poole and Jones 2005).

Function of SHP-1 Domains, Regulation of SHP-1 Activity and Targets

The different domains of SHP-1 protein have specific functions. Crystallographic study revealed that the N-SH2 is bound to the catalytic site in resting state of the protein. The interaction of N-SH2 and the PTP domain is achieved via charge-charge interaction and has a bidirectional inhibitory effect. Thus, N-SH2 inhibits PTP activity, and the catalytic domain impedes the binding of the N-SH2 with phospho-tyrosil targets. On the other hand, C-SH2 has a minimum interaction with the PTP domain. The latter information indicates that C-SH2 can effectively serve as a sensor for the targeted phosphotyrosine residue. Once activated, the protein changes its conformation and releases the phosphopeptide-binding pocket of N-SH2 as well as the catalytic site of the PTP domain (Poole and Jones 2005).

SH2 domains of SHP-1 interact with phospho-tyrosil residues present in different molecules such as scaffold proteins, receptor tyrosine kinases (RTKs), cytokine receptors, and immune inhibitory receptors. The latter are transmembrane proteins with the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) or the immunoreceptor tyrosine-based switch motif (ITSM). ITIMs contains six amino acid stretch - V/L/IxpYxxL/V whereas ITSM, TxpYxxV/I, which are phosphorylated upon receptor stimulation and recruits SHP-1. A combinatorial phospho-tyrosine study revealed that SHP-1 C-SH2 domain binds selectively to (V/I/L)xpYAx(LV), whereas N-SH2 to LxpY(M/F)x(F/M) and LXpYAXL. In addition, N-SH2 binding can be increased with hydrophobic or positively charged residue at the position pY+4 and/or pY+5 (Pao et al. 2007; Lorenz 2009). It has been reported that several kinases of the JAK, IKK, and MAP kinase families have similar ITIM motif found mainly in the catalytic domain of the kinase allowing SHP-1 to interact with the kinase via a kinase tyrosine-based inhibitory motifs (KTIM) (Abu-Dayyeh et al. 2008) and therefore conferring a better regulation over the kinase activity at resting state.

In addition to SH2 domains, the C-terminal of SHP-1 also controls its activity. As stated above, the C-terminal region contains two tyrosil (Y536 and Y564) and one serine (S591) residues. The phosphorylation of Y536 upon insulin stimulation or apoptosis inducer reagent increases SHP-1 activation in lymphoblast, ovary, hepatoma, and monocytic cell lines. It was observed an increase between 4–8 folds of Y564 phosphorylation concomitant with a 1.6-fold augmented activity of the PTP by using a protein ligation approach to install a nonhydrolyzable phosphomimetic (phosphonate) analog on Y536 and Y564 of SHP-1. On the other hand, phosphorylation of S591 negatively regulates SHP-1 activity. In human platelets SHP-1 is constitutively associated with protein kinase C (PKC) alpha and Vav1, inhibiting Vav1 function. However, when platelets are activated via thrombin receptor, PKCα is activated and phosphorylate the S591 residue of SHP-1 inhibiting its activity; consequently Vav1 is phosphorylated. In addition to the negative regulation of SHP-1, S591 phosphorylation is also involved in determining its subcellular localization. T cells that phosphorylated S591-SHP-1 displayed a reduced translocation to lipid raft and nuclear compartment. S591 phosphorylation has been implicated in the negative regulation of SHP-1 and its nuclear translocation in response to hypertonic solution (Poole and Jones 2005; Lorenz 2009). To sum up, while phosphorylation of C-terminal of SHP-1 in S591 appears to regulate negatively the phosphatase, phosphorylation of Y536 and Y564 residues increase its activity.

Once activated, the catalytic domain of SHP-1 is freed and dephosphorylates its substrate by releasing phosphate. The catalytic domain of SHP-1 contains the PTP signature motif (I/V)HCxxGxxR(S/T) with an essential cysteinyl residue that can mediate hydrolysis via a thio-phosphate intermediate formation. SHP-1 can be reversibly inactivated when the cysteine residue is oxidized by reactive oxygen species (ROS). Oxidized PTP domain can be reactivated via glutathione or thioredoxin pathway (Pao et al. 2007). Gomez et al. (2010) elegantly demonstrated a new negative regulation of SHP-1 activity, as well as other PTPs, mediated by iron (Fig. 3). The iron dicitrate complex was found to compete with phosphotyrosine substrate for the catalytic pocket of the PTP, leading to inhibition of PTPs and increasing of MAPK signaling pathway. In this line of though, SHP-1 activity can be self-regulated, regulated by external oxidation or mechanism involving iron.
PTPN6, Fig. 3

Computational docking of SHP-1 and phosphotyrosil substrate/iron citrate complexes. (a) Docking experiment depicts that the dicitrate iron complex C7 [Fe(Cit)2]5- (shown by arrow) resides in the catalytic pocket (light green/red) of SHP-1 (PDB code: 1GWZ). (b) In vitro cocrystallization of SHPS-1 (PDB code: 1FPR) and tyrosine phospho-peptide substrate pY459 (red) exclude the C7 complex (red/green/gray color sticks), suggesting a possible competition between C7 complex and the phospho-tyrosil peptide for the catalytic pocket (light green/purple)

Concerning the target of SHP-1, this phosphatase can regulate many signaling pathways triggered by different receptors such as T cell receptor (TCR), B cells receptor (BCR), toll-like receptors (TLR), and NOD-like receptors. In T cells, SHP-1 has been shown to directly regulate the TCR or associated co-receptor; however, the exact mechanism is unclear. It has been proposed as an antagonism mechanism of SHP-1. A study done with T cells bearing TCR with different specificity revealed that stimulation of these cells with an agonist protein for one receptor and an antagonist to a second receptor lead to the binding of Lck to the agonist-activated receptor, whereas SHP-1 is recruited to the antagonist-activated TCR. In addition, in the presence of weak antigen Lck phosphorylates SHP-1 on Y564 residue, recruiting SHP-1 to associate and dephosphorylate Lck. However, in the presence of a strong ligand binding, ERK is activated and phosphorylates Lck, in this way Lck does not interact with SHP-1 and triggered signaling continues (Pao et al. 2007; Lorenz 2009). Other SHP-1 substrates such as Zap-70, SLP-76, PI3K, STAT-3, and Vav have been proposed. As some of the latters substrates and other important signaling molecules are localized constitutively or after stimulation in the lipid raft as well as SHP-1. In T cells, around 20–30% of SHP-1 is found constitutively in the lipid raft and has a negative regulation role on Lck phosphorylation and IL-2 production. Furthermore, T cells express inhibitory receptors such as the carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1), the cytotoxic T-lymphocyte antigen-4 (CTLA4), PD1, and the leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) that can recruit or are constitutively associated with SHP-1, resulting in its activation and consequent inhibition of T cells signaling and function (Lorenz 2009; Stanford et al. 2012). SHP-1 has been implicated in the T-cell development. Early studies showed that the presence of SHP-1 in thymocytes set the threshold of positive and negative selection; thus, SHP-1-deficient thymocytes displayed a higher response to TCR stimulation leading to increase in positive and negative selection (Stanford et al. 2012). Further studies with CD4+ T cell-specific deletion of SHP-1 revealed that SHP-1 was not necessary for the positive and negative selection of thymocytes; however, its presence was required to limit the IL-4-mediated Th2 phenotype and memory T-cells (Johnson et al. 2013). Recently, it was shown with the same conditional deletion of SHP-1 in CD4+ T-cells that the presence of SHP-1 was important to maintain the mature repertory of CD4+ and CD8+ T-cells in the secondary organs (Martinez et al. 2016).

SHP-1 is also known to regulate BCR. BCR activation results in a phosphorylation of many signaling pathways such as the SRC kinase’s members, Lyn and Fyn, the spleen tyrosine kinase (SYK), phospholipases, and so on. Lyn has an inhibitory effect upon BCR activation as it phosphorylates many inhibitory receptors, for instance, CD22, CD72, CD5, and paired Ig-like receptor (PIR-B). These phosphorylated receptors recruit and activate SHP-1, inhibiting the BCR-triggered signaling. For instance, CD22 is an ITIM-containing receptor member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family that is phosphorylated by Lyn. CD22 associates and negatively regulates BCR response via SHP-1, as in CD22 or SHP-1-deficient B cells were found to display higher intracellular calcium mobilization and IgM secretion. Lyn-CD22-SHP-1 pathway is present at mature B-cells and is involved in the development of B cell tolerance. Later on, it was shown that autoreactive B-cell tolerance requires CD11b, a variant of the integrin-α-2, as CD11b-deficient B-cells showed decreased CD22 and Lyn phosphorylation as well as SHP-1 recruitment. CD11b-deficient mice developed high title of autoantibody and immune-complex deposition in the kidney. Many other SHP-1 substrates have been described such as PI3K, Vav, Btk, SLP-76/65, Syk, and 3BP2 in B cells and transcription factors, for instance, ETs; low levels of ETs activation is essential for B-cell differentiation to plasma cells. In addition, SHP-1 activity is downregulated in activated B cells, suggesting that SHP-1 in resting cells is active through unknown mechanism. The production of ROS has been proposed as a mechanism of transient negative modulation of SHP-1 activity in activated B cells. Another mechanism is the constitutive association of SHP-1 with BCR in resting B-cells in the germinal center that is broken in activated B cells; thus, the presence of SHP-1 in B-cells was essential for the existence of the germinal center (Tsubata 2012; Luo et al. 2014).

Concerning TLR signaling, there are few studies showing the negative regulation of TLR-triggered pathway by SHP-1. Initially, it has been demonstrated in an infectious experimental model that SHP-1 associates and rapidly inhibits the interleukin-1 receptor-associated kinase 1 (IRAK-1) and LPS-mediated macrophage functions upon TLR4 stimulation, as well as in response to other ligands targeting other TLRs utilizing IRAK-1 in their signaling cascades. SHP-1 was found to interact with an evolutionarily conserved KTIM motif on IRAK-1 (Abu-Dayyeh et al. 2008). On the other hand, this association of SHP-1 and IRAK-1 resulted in an augmented production of interferon type I by macrophages dependent on the intracellular receptor RIG-1 (An et al. 2008). Many of the inhibitory receptors described above can also regulate TLR signaling, by recruiting and activating SHP-1. Among others, the CD22 inhibits TLR9-triggered pathway in B-cells; the CEACAM1 down modulated the activation of TLR4 in neutrophils and TLR2 in human pulmonary leukocyte cells (Van Avondt et al. 2015); and CD300a and CD300f negatively regulated TLR9 and TLR3, respectively, in macrophages cell lines (Kim et al. 2012).

SHP-1 and Diseases

As discussed above, studies demonstrating implication of SHP-1 in different diseases has been based in part on phenotypes observed in “me” or “mev” mice. These mice are known to spontaneously develop inflammatory abnormalities in multiple organs such as skin, kidney, and lungs, which drive attention to certain diseases such as respiratory disorders. Of utmost interest, involvement of SHP-1 in cancer, infectious diseases, and diabetes has been reported and will be discussed in the following sections.

Respiratory Diseases

Studies done with “mev” mice revealed higher infiltration of macrophages, eosinophils as well as neutrophils, and lymphocytes in the lungs. These mice developed an allergic-type inflammatory response similar to allergic asthma, including mucus hyperproduction, metaplasia of Goblet cells, and increased airway hyperresponsiveness. Additionally, the concentration of Th2-type cytokines such as IL-4, IL-5, and IL-13 was found to be elevated, as well as chemokines (CCL2/MCP-1 and CCL11/eutaxin) that are important for recruitment of monocytes and eosinophils. As Th2 response seemed to be predominant in “mev” mice, further investigation on mast cells was done due to their capacity to produce IL-4 and IL-13, comparable to basophils and eosinophils. In vitro study using IL-13 as grown factor showed that cells from “mev” mice grow less than their WT counterpart indicating that SHP-1 controls the number of mast cells progenitors (c-kit/FcγRI double-positive cells) and its maturation. Furthermore, mast cells from these mice were found to be resistant for apoptosis, possibly due to increased expression of the anti-apoptosis gene Bcl2. In vitro experiments with mast cells from “mev” mice showed higher production of IL-4 and IL-5 in response to superoxide, as well as the spontaneous production of those cytokines being dependent on ROS production. The role of ROS in the regulation of SHP-1 activity is well known; therefore it is not surprising that it could regulate the residual 20% of SHP-1 activity found in cells from “mev” mice. In addition to cytokines, SHP-1 also regulates mast cell degranulation as revealed by bone marrow-derived mast cells from “mev” mice that spontaneously releases β-hexosaminadase and has greater response to IgE stimulation in comparison to WT cells. In conclusion, in experimental models SHP-1 seems to modulate lung disorders; however, correlation of human lungs disease and SHP-1 expression has not been still found. Nevertheless, low expression of SHP-1 has been correlated with human chronic myeloid leukemia and psoriasis (Zhu et al. 2010).


SHP-1 negatively regulates intracellular signaling necessary to many cellular functions including cell growth and division. For instance, JAK/STAT and PI3K/AKT pathways are under control of SHP-1. Therefore, it is not surprising that many cancer cells have been found not to express SHP-1. For instance, cell lines derived from T cell, B cell, and natural killer (NK) cell lymphomas (all classified as non-Hodgkin’s lymphomas), as well as leukemia, were found in majority not to express or to have a reduced expression of SHP-1. However, some other cancerous cell lines such as BJAB, HUT102B, HUB102B2, AG876BL, KK124, Kem III, and WW1BL do indeed express SHP-1. Expression of SHP-1 in lymphoma is related with the progression, aggressivity, and the stage at which cells are (Wu et al. 2003). Clinically, analysis of 207 patient samples having different malignant lymphomas/leukemia revealed that 100% of NK/T cell lymphomas and 95% of samples from patients with malignant lymphomas bore complete abrogation of SHP-1 expression. One mechanism found to be responsible for the latter event is the methylation of PTPN6 promoter. DNA methyl-transferase together with STAT3 and histone diacetylase I promote the silencing of SHP-1 in lymphoma and leukemia cells. However, methylation of PTPN6 promoter might not be the only mechanism as treatment with demethylation drug, 5-deoxyazacytidine, increased SHP-1 RNA, but not protein expression, suggesting that other posttranscriptional modification of SHP-1 could be involved (Wu et al. 2003; Tsui et al. 2006; Sharma et al. 2016). Nevertheless, abrogated SHP-1 expression was also related to CEP-701 (Lestaurtinib)-induced resistant lymphoblast as reexpression of SHP-1 reverted the resistance. This multitargeted protein kinase inhibitor induces remission of acute myeloid leukemia. Thus, SHP-1 agonists might be useful for the cancer therapy. Indeed, Regorafenib, recently approved for treatment of metastatic colorectal cancer and advanced gastrointestinal stromal tumor, is a multi-receptor tyrosine kinase inhibitor that acts as SHP-1 agonist by dissociating the N-SH2 from catalytic domain of the phosphatase and consequently increasing its activity. Drugs derived from Sorafenib or Fluora-sorafenib (Regorafenib), for instance SC-43, SC-78, and SC-60, showed a better effect as SHP-1 agonist and might be useful for treatment of human colorectal cancer, metastatic triple-negative breast cancer, and hepatocellular carcinoma. Polytherapy has been proposed to overcome Sorafenib resistance, for example, the combination with SC-2001, a structural analog of Mcl-inhibitor, that upregulates the transcriptor factor for SHP-1 in colorectal and breast cancer; as well as the combination with YC-1, a soluble cyclase activator, that inhibits cell-cycling involved kinases. Many other drugs that increase SHP-1 activity or expression has been used for cancer therapy (for review (Sharma et al. 2016)).

In contrast to hematopoietic cancer, SHP-1 protein and RNA expression are increased in epithelial ovarian, breast tumor, and nasopharyngeal carcinoma cells. Particularly in prostate cancer, SHP-1 expression and activity is related with the production of somatostatin that has a paracrine/autocrine inhibitory effect on cells proliferation via SHP-1 (Wu et al. 2003). High SHP-1 expression, controlled by low methylation of PTPN6 promoter, was correlated with the poor survival and resistance to therapy of high-grade glioma patients (Sooman et al. 2014). In this way, SHP-1 expression is related with proliferation and aggressiveness. Interestingly, it has been reported in the last few years that the use of PTP inhibitors such as peroxovanadium can greatly abrogate the progression of ovarian cancer in mice (Caron et al. 2008). Another anti-Leishmania’s drug, the sodium stibogluconate, showed a SHP-1 inhibiting activity, and it was target for solid tumor clinical trials in combination with interferons or chemotherapy, which resulted in several adverse side effects in up to 68% of the patients. To overcome the infusion inconvenience of sodium stibogluconate a small-aromatic compound was developed, which showed to be around 50 times more efficient than sodium stibogluconate. However, the phase II of the latter study was not complete (Watson et al. 2016). Other obstacle for drug therapy based on phosphatase inhibitors is the specificity for SHP-1 and not for other intracellular phosphatase.

Infectious Diseases

As stated above concerning cancer, SHP-1 has an important antiproliferative function; in this line of thought its absence is essential for the progression of the disease. However, during the course of certain infectious diseases, it has been found that the negative regulatory action of SHP-1 can be exploited by pathogens to favor their survival and development into the host cells. Two examples are the intracellular pathogens of Leishmania genus and Mycobacterium tuberculosis known to infect phagocytes of the monocyte/macrophage lineage. These cells play a critical role in innate immune response being responsible to engulf invading microorganisms and to terminate them. Macrophages display many microbicidal molecules such as ROS, nitric oxide (NO), and pro-inflammatory mediators. Even with such an impressive defense system, they can become infected by different intracellular parasites, as mentioned above. In the case of Leishmania, a protozoan parasite responsible for causing leishmaniasis, this parasite is known to interact with macrophages and to rapidly inactivate the IFNγ-inducible kinase JAK-2, as well as several members of the MAP kinase family, and the LPS-induced IRAK-1 kinase (critical TLR pathway). These multiple signaling alterations result in the inhibition of several macrophages microbicidal functions. One of the mechanisms exploited by the parasite is the inactivation of the host cell by inducing macrophage SHP-1 activity upon its C-terminal portion cleavage by Leishmania metalloprotease GP63 (Gomez et al. 2009). Activation of SHP-1 could be achieved with GP63-containing microvesicles secreted by the parasite upon temperature shift (Hassani et al. 2011). In addition to alter SHP-1 activity, infection with Leishmania increased expression of the host phosphatase protein by a mechanism dependent on the interaction of the sialic acid and Siglec-1 from the parasite and host cells, respectively (Roy and Mandal 2016). Interestingly, as mentioned above in the text, SHP-1 was found to interact with an evolutionarily conserved kinase tyrosyl-based inhibitory motif (KTIM) being present in various kinases such as JAK-2, IRAK-1, and ERK-1/2, all being targeted by SHP-1 inhibitory action upon Leishmania infection (Abu-Dayyeh et al. 2008). SHP-1 activity and inhibition of IRAK-1, in late infection by L. donovani parasites, was positively modulated by the transforming grown factor (TGF) (Das et al. 2012). The role of SHP-1 in Leishmaniasis has been further demonstrated in an experimental model by a pharmacological intervention using the bis-peroxovanadium bpV(phen) and genetically using the “mev” mice. Treatment of mice with PTP inhibitors reduced both parasite load and skin lesion of L. major-infected mice and completely protected mice from the visceral L. donovani infection. The same phenotype was observed in “mev” mice, which developed a significantly reduced cutaneous lesion (Mansfield and Olivier 2001). L. chagasi-mediated Leishmaniasis visceral patient presents a defect to concentrate urine that was related with the activation of SHP-1 and its effect on the transcription factor that regulated the expression of many urine-concentrate factors (Zhou et al. 2014). Thus, SHP-1 is a key player in the establishment of the Leishmania parasite infection and pathogeneses.

Another intramacrophage pathogen is the bacteria Mycobacterium tuberculosis, which is the causative agent of tuberculosis. This bacterium enters through the respiratory airway and infects the lungs macrophages. How the bacillus survives inside of the macrophages is not very clear. It has been proposed that M. tuberculosis inhibits the macrophage functions by the action of its bacterial cell wall glycolipid (LAM). LAM was reported to inhibit ERK1/2 kinase by the activation of SHP-1 (Nandan et al. 2000). LAM was also found to inhibit M. tuberculosis-induced apoptosis and to involve SHP-1, as LAM-induced apoptosis was shown to be absent in SHP-1 deficient “me” cells. This latter effect was shown to be related with increased LAM-induced NO production in absence of SHP-1 (Rojas et al. 2002).

In addition to those pathogens, filarial nematodes can release excretory-secretory products (ES) influencing the immune cell functions. The ES is secreted by majority of filarial nematodes affecting human including Wuchereria bancrofti, Brugia malayi, and Onchocerca volvulus, and by Acanthocheilonema viteae affecting rodents. ES protein has been found to inhibit the B cell functions by inducing SHP-1 recruitment to the BCR and therefore altering its signaling activity (Mansfield and Olivier 2001).

Glucose Metabolism (Diabetes)

Diabetes mellitus is described as a defect in the glucose metabolism, hence hyperglycemia, because of insufficient production of insulin or its tolerance. The role of SHP-1 in the glucose homeostasis and diabetes-related pathology has been explored. A study using “mev” mice demonstrated that in the normal condition SHP-1 collaborates to the insulin resistance profile due to its negative modulation of the insulin receptor substrate-1 (IRS-)-related signaling pathway PI3K/AKT, possibly by modulating PTEN. Furthermore, SHP-1 was also found to downregulate the transmembrane glycoprotein carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) that controls insulin clearance. Liver cells from “mev” showed a hyperphosphorylation of CEACAM-1. This adhesion molecule is also co-immunoprecipitated with SHP-1. Furthermore, SHP-1, but not PTP1B or PTP-PEST, can specifically dephosphorylate CEACAM-1. In vivo experiment showed a slower clearance of radiolabeled insulin in “mev” mice favoring the increase of glucose (Dubois et al. 2006). SHP-1 transcription is regulated by the transcriptor factor – PREP-1 – that is overexpressed in the diet- or genetic-manipulated obesity mice. Thus, SHP-1 expression is higher in metabolic tissue. Mice with SHP-1-specific deletion in liver cells developed obesity when they received high fat diet and they are protected from liver, but not peripheral, insulin resistance. In addition, SHP-1 controls insulin effect on muscle cells; introduction of dominant negative-SHP-1 in myocytes revealed that SHP-1 negatively regulated glucose uptake and glycogen synthesis by a mechanism involving the AKT phosphorylation and glucose transporter type 4 expression (Xu et al. 2014).

One common diabetic consequence is the retinopathy and other microvascular complications due to a hyperglycemia-induced apoptosis process. The latter involves the activation of PKCα that regulates NF-κB activation (via ROS generation) and p38 MAPK. This MAPK induces SP-1 activation and consequently enhancement in the SHP-1 expression. SHP-1 negatively regulates the pro-survival growth factor receptor – PDGFR-β – resulting in pericyte apoptosis (Geraldes et al. 2009).


Collectively, it is possible to conclude that SHP-1 – a member of the PTPs superfamily – is a critical negative regulatory phosphatase of kinases controlling several functions of immune cells. Its involvement in the development of many diseases, such as cancer, allergy, diabetes, and infection diseases, has been clearly established and found to be related to its inability to perform its regulatory functions or to be exploited by pathogens to evade immune responses. An in-depth understanding on how it is regulated could bring about the discovery of very innovative ways to treat various pathologies.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Health Science programUniversidade Santo Amaro, programa de Ciência da SaúdeSão PauloBrazil
  2. 2.Infectious Diseases and Immunity in Global Health (IDIGH) ProgramResearch Institute of McGill University Health CentreMontrealCanada