Strategy for Leukemia Treatment Targeting SHP-1,2 and SHIP

Protein tyrosine phosphatases (PTPs) are modulators of cellular functions such as differentiation, metabolism, migration, and survival. PTPs antagonize tyrosine kinases by removing phosphate moieties from molecular signaling residues, thus inhibiting signal transduction. Two PTPs, SHP-1 and SHP-2 (SH2 domain-containing phosphatases 1 and 2, respectively) and another inhibitory phosphatase, SH2 domain-containing inositol phosphatase (SHIP), are essential for cell function, which is reflected in the defective phenotype of mutant mice. Interestingly, SHP-1, SHP-2, and SHIP mutations are identified in many cases of human leukemia. However, the impact of these phosphatases and their mutations regarding the onset and progression of leukemia is controversial. The ambiguity of the role of these phosphatases imposes challenges on the development of targeting therapies for leukemia. This fundamental problem, confronted by the expanding investigational field of leukemia, will be addressed in this review, which will include a discussion of the molecular mechanisms of SHP-1, SHP-2, and SHIP in normal hematopoiesis and their role in leukemia. Clinical development of leukemic therapies achieved by targeting these phosphatases will be addressed as well.

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MOLECULAR MECHANISMS OF DEVELOPMENT OF CEREBRAL TOLERANCE TO ISCHEMIA (REVIEW. PART 2)

Annals of the Russian academy of medical sciences ◽

10.15690/vramn.v67i7.336 ◽

2012 ◽

Vol 67 (7) ◽

pp. 20-29

Author(s):

E. V. Shlyakhto ◽

E. R. Barantsevich ◽

N. S. Shcherbak ◽

M. M. Galagudza

Keyword(s):

Vascular Reactivity ◽

Molecular Mechanisms ◽

Cell Function ◽

Regional Blood Flow ◽

Ion Homeostasis ◽

Antioxidant Systems ◽

Ischemic And Reperfusion Injury ◽

Mechanisms Of Development ◽

Endogenous Antioxidant ◽

The Impact

In the 2nd part the authors describe in details the main aspects of protective effect of preconditioning of the brain: inhibition of programmed cell death, weakening of phenomenon of excitotoxicity, activation of endogenous antioxidant systems, anti-inflammatory effects, modulation of glial cell function, changes in regional blood flow and vascular reactivity. In addition, data analysis on the impact of preconditioning on brain neurogenesis, the state of the blood-brain barrier, ion homeostasis and metabolism of neurons is presented. Review emphasizes the role of microRNAs in mechanisms of ischemic tolerance of brain. Profound understanding of molecular mechanisms of increased tolerance of brain to ischemic and reperfusion injury requires the implementation of this phenomenon in clinical practice.

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The Paradigm of Targeting an Oncogenic Tyrosine Kinase: Lesson from BCR-ABL

10.5772/intechopen.97528 ◽

2021 ◽

Author(s):

Enrico Bracco ◽

M. Shahzad Ali ◽

Stefano Magnati ◽

Giuseppe Saglio

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinases ◽

Molecular Mechanisms ◽

Kinase Activity ◽

Fusion Gene ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Protein Tyrosine Phosphatases ◽

Selective Inhibition ◽

Tyrosine Kinase Activity

The aberrant tyrosine phosphorylation, either due to constitutive tyrosine kinases (TKs) or to inactivation of protein tyrosine phosphatases (PTPs), is a widespread feature of many cancerous cells. The BCR-ABL fusion protein, which arises from the Philadelphia chromosome, is a molecular distinct and peculiar trait of some kind of leukemia, namely Chronic Myeloid and Acute Lymphoblastic Leukemia, and displays constitutive tyrosine kinase activity. In the chapter, we will highlight the milestones that had led to the identification of the BCR-ABL fusion gene and its role as the only molecular pathogenic event sufficient to elicit and sustain chronic myeloid leukemia. We will also discuss the effort made to unveil the molecular mechanisms of action of the chimeric tyrosine kinase that eventually lead to aberrant cell proliferation and impaired cell-death. Furthermore, we will also review the lesson learned from the selective inhibition of BCR-ABL which currently represent a breakthrough in the treatment of several tumors characterized by defective tyrosine kinase activity.

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Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences

Molecular and Cellular Biology ◽

10.1128/mcb.12.5.2396-2405.1992 ◽

1992 ◽

Vol 12 (5) ◽

pp. 2396-2405

Author(s):

R J Matthews ◽

D B Bowne ◽

E Flores ◽

M L Thomas

Keyword(s):

Signal Transduction ◽

Glutamic Acid ◽

Tyrosine Kinases ◽

Protein Tyrosine Phosphatases ◽

Sh2 Domain ◽

Tyrosine Phosphatases ◽

Protein Tyrosine ◽

Sh2 Domains

Protein tyrosine phosphatases (PTPases) are a family of enzymes important in cellular regulation. Characterization of two cDNAs encoding intracellular PTPases expressed primarily in hematopoietic tissues and cell lines has revealed proteins that are potential regulators of signal transduction. One of these, SHP (Src homology region 2 [SH2]-domain phosphatase), possesses two tandem SH2 domains at the amino terminus of the molecule. SH2 domains have previously been described in proteins implicated in signal transduction, and SHP may be one of a family of nonreceptor PTPases that can act as direct antagonists to the nonreceptor protein tyrosine kinases. The SH2 domains of SHP preferentially bind a 15,000-Mr protein expressed by LSTRA cells. LSTRA cells were shown to express SHP protein by immunoprecipitation, thus demonstrating a potential physiological interaction. The other PTPase, PEP (proline-, glutamic acid-, serine-, and threonine-rich [PEST]-domain phosphatase), is distinguished by virtue of a large carboxy-terminal domain of approximately 500 amino acids that is rich in PEST residues. PEST sequences are found in proteins that are rapidly degraded. Both proteins have been expressed by in vitro transcription and translation and in bacterial expression systems, and both have been demonstrated to have PTPase activity. These two additional members of the PTPase family accentuate the variety of PTPase structures and indicate the potential diversity of function for intracellular tyrosine phosphatases.

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The Tyrosine Kinase-Binding and Proline-Rich Domains of Mutant CBL Are Essential for Leukemogenesis

Blood ◽

10.1182/blood.v126.23.2457.2457 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2457-2457

Author(s):

Scott Nadeau ◽

Wei An ◽

Gulzar Ahmad ◽

Bhopal Mohapatra ◽

Neha Zutshi ◽

...

Keyword(s):

Tyrosine Kinase ◽

Progenitor Cells ◽

Molecular Mechanisms ◽

Sh2 Domain ◽

Leukemia Cell Line ◽

Hematopoietic Stem ◽

Rich Domain ◽

The Impact ◽

Cbl Proteins

Abstract Mutations of the tyrosine kinase-directed ubiquitin ligase CBL are associated with myeloid malignancies, yet the molecular mechanisms by which this tumor suppressor becomes a dominant oncogene to initiate the leukemogenic process are unclear. In this study, we used systematic mutagenesis to delineate the importance of the various protein-protein interaction domains/motifs of a CBL mutant that is most frequently found in human leukemias, Y371H, in inducing leukemogenesis. We tested the impact of these secondary mutations on the ability of CBL-Y371H to impart hypersensitivity to cytokines and to upregulate the associated signaling pathways in the TF1 leukemia cell line model, and in mouse hematopoietic stem/progenitor cells from Cbl-null mice to mimic the lack of wildtype CBL expression in most of the mutant CBL bearing leukemia patients. The secondary mutations included: Cbl G306E, to abrogate the ability of the TKB domain of mutant Cbl to bind to activated tyrosine kinases; internal deletion of the proline-rich domain (AA 477-688) to abrogate interactions with SH3 domain containing partners; Cbl-Y700/731/774F triple phosphorylation site mutant predicted not to interact with the SH2 domain-containing partners; and Cbl-1-436 deletion construct lacking all C-terminal motifs. Analyses of stably expressed mutants in TF-1 cells for hypersensitivity to SCF1 demonstrated an essential role of an intact TKB domain and a particularly important role of the proline-rich domain. Transient retroviral expression in Cbl-null primary murine hematopoietic stem/progenitor cells confirmed these results. Deletion of the proline-rich domain led to substantially less tyrosine phosphorylation of the oncogenic mutant Cbl as well as of the c-Kit receptor upon SCF stimulation, and cells expressing this mutant lacked the sustained activation of Erk1/2 and Akt typically seen after SCF stimulation of the Cbl-Y371H-expressing cells. Together, our data provide conclusive evidence that interaction of leukemogenic mutant Cbl proteins with the upstream tyrosine kinase (via the TKB domain) and with partner proteins (via the proline-rich domain) provides a basic mechanism for gain of function phenotype of mutant Cbl proteins. Our studies suggest that identification of the leukemogenesis-critical partners of the proline-rich domain and targeting of the TKB-tyrosine kinase interface provide new therapeutic approaches against mutant Cbl-driven leukemias. Disclosures No relevant conflicts of interest to declare.

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Schistosome immunomodulators

PLoS Pathogens ◽

10.1371/journal.ppat.1010064 ◽

2021 ◽

Vol 17 (12) ◽

pp. e1010064

Author(s):

Sreemoyee Acharya ◽

Akram A. Da’dara ◽

Patrick J. Skelly

Keyword(s):

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Cell Metabolism ◽

Natural Infection ◽

Host Cells ◽

Anionic Polymer ◽

Th2 Response ◽

Anti Inflammatory ◽

The Impact

Schistosomes are long lived, intravascular parasitic platyhelminths that infect >200 million people globally. The molecular mechanisms used by these blood flukes to dampen host immune responses are described in this review. Adult worms express a collection of host-interactive tegumental ectoenzymes that can cleave host signaling molecules such as the “alarmin” ATP (cleaved by SmATPDase1), the platelet activator ADP (SmATPDase1, SmNPP5), and can convert AMP into the anti-inflammatory mediator adenosine (SmAP). SmAP can additionally cleave the lipid immunomodulator sphingosine-1-phosphate and the proinflammatory anionic polymer, polyP. In addition, the worms release a barrage of proteins (e.g., SmCB1, SjHSP70, cyclophilin A) that can impinge on immune cell function. Parasite eggs also release their own immunoregulatory proteins (e.g., IPSE/α1, omega1, SmCKBP) as do invasive cercariae (e.g., Sm16, Sj16). Some schistosome glycans (e.g., LNFPIII, LNnT) and lipids (e.g., Lyso-PS, LPC), produced by several life stages, likewise affect immune cell responses. The parasites not only produce eicosanoids (e.g., PGE2, PGD2—that can be anti-inflammatory) but can also induce host cells to release these metabolites. Finally, the worms release extracellular vesicles (EVs) containing microRNAs, and these too have been shown to skew host cell metabolism. Thus, schistosomes employ an array of biomolecules—protein, lipid, glycan, nucleic acid, and more, to bend host biochemistry to their liking. Many of the listed molecules have been individually shown capable of inducing aspects of the polarized Th2 response seen following infection (with the generation of regulatory T cells (Tregs), regulatory B cells (Bregs) and anti-inflammatory, alternatively activated (M2) macrophages). Precisely how host cells integrate the impact of these myriad parasite products following natural infection is not known. Several of the schistosome immunomodulators described here are in development as novel therapeutics against autoimmune, inflammatory, and other, nonparasitic, diseases.

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Regulation of the Jak2 Tyrosine Kinase by Its Pseudokinase Domain

Molecular and Cellular Biology ◽

10.1128/mcb.20.10.3387-3395.2000 ◽

2000 ◽

Vol 20 (10) ◽

pp. 3387-3395 ◽

Cited By ~ 219

Author(s):

Pipsa Saharinen ◽

Kati Takaluoma ◽

Olli Silvennoinen

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinases ◽

Protein Tyrosine Phosphatases ◽

Kinase Domain ◽

Sh2 Domain ◽

Tyrosine Kinase Domain ◽

Functional Roles ◽

Domain Of Unknown Function ◽

Ligand Stimulation ◽

Induced Aggregation

ABSTRACT Activation of Jak tyrosine kinases through hematopoietic cytokine receptors occurs as a consequence of ligand-induced aggregation of receptor-associated Jaks and their subsequent autophosphorylation. Jak kinases consist of a C-terminal tyrosine kinase domain, a pseudokinase domain of unknown function, and Jak homology (JH) domains 3 to 7, implicated in receptor-Jak interaction. We analyzed the functional roles of the different protein domains in activation of Jak2. Deletion analysis of Jak2 showed that the pseudokinase domain but not JH domains 3 to 7 negatively regulated the catalytic activity of Jak2 as well as Jak2-mediated activation of Stat5. Phosphorylation of Stat5 by wild-type Jak2 was dependent on the SH2 domain of Stat5; however, this requirement was lost upon deletion of the pseudokinase domain of Jak2. Investigation of the mechanisms of the pseudokinase domain-mediated inhibition of Jak2 suggested that this regulation did not involve protein tyrosine phosphatases. Instead, analysis of interactions between the tyrosine kinase domain and Jak2 suggested that the pseudokinase domain interacted with the kinase domain. Furthermore, coexpression of the pseudokinase domain inhibited the activity of the single tyrosine kinase domain. Finally, deletion of the pseudokinase domain of Jak2 deregulated signal transduction through the gamma interferon receptor by significantly increasing ligand-independent activation of Stat transcription factors. These results indicate that the pseudokinase domain negatively regulates the activity of Jak2, probably through an interaction with the kinase domain, and this regulation is required to keep Jak2 inactive in the absence of ligand stimulation. Furthermore, the pseudokinase domain may have a role in regulation of Jak2-substrate interactions.

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Phosphatidylinositol 3-Kinase p85α Subunit-Dependent Interaction with BCR/ABL-Related Fusion Tyrosine Kinases: Molecular Mechanisms and Biological Consequences

Molecular and Cellular Biology ◽

10.1128/mcb.25.18.8001-8008.2005 ◽

2005 ◽

Vol 25 (18) ◽

pp. 8001-8008 ◽

Cited By ~ 17

Author(s):

Shu-yue Ren ◽

Elisabeth Bolton ◽

M. Golam Mohi ◽

Andrea Morrione ◽

Benjamin G. Neel ◽

...

Keyword(s):

Tyrosine Kinases ◽

Molecular Mechanisms ◽

Bone Marrow Cells ◽

Point Mutations ◽

Sh2 Domain ◽

Catalytic Subunit ◽

Protein Network ◽

Phosphatidylinositol 3 Kinase ◽

Murine Bone Marrow ◽

Phosphatidylinositol 3

ABSTRACT The p85α subunit of phosphatidylinositol 3-kinase (PI-3k) forms a complex with a protein network associated with oncogenic fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGFβR, and NPM/ALK, resulting in constitutive activation of the p110 catalytic subunit of PI-3k. Introduction of point mutations in the N-terminal and C-terminal SH2 domain and SH3 domain of p85α, which disrupt their ability to bind phosphotyrosine and proline-rich motifs, respectively, abrogated their interaction with the BCR/ABL protein network. The p85α mutant protein (p85mut) bearing these mutations was unable to interact with BCR/ABL and other FTKs, while its binding to the p110α catalytic subunit of PI-3k was intact. In addition, binding of Shc, c-Cbl, and Gab2, but not Crk-L, to p85mut was abrogated. p85mut diminished BCR/ABL-dependent activation of PI-3k and Akt kinase, the downstream effector of PI-3k. This effect was associated with the inhibition of BCR/ABL-dependent growth of the hematopoietic cell line and murine bone marrow cells. Interestingly, the addition of interleukin-3 (IL-3) rescued BCR/ABL-transformed cells from the inhibitory effect of p85mut. SCID mice injected with BCR/ABL-positive hematopoietic cells expressing p85mut survived longer than the animals inoculated with BCR/ABL-transformed counterparts. In conclusion, we have identified the domains of p85α responsible for the interaction with the FTK protein network and transduction of leukemogenic signaling.

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Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences.

Molecular and Cellular Biology ◽

10.1128/mcb.12.5.2396 ◽

1992 ◽

Vol 12 (5) ◽

pp. 2396-2405 ◽

Cited By ~ 246

Author(s):

R J Matthews ◽

D B Bowne ◽

E Flores ◽

M L Thomas

Keyword(s):

Signal Transduction ◽

Glutamic Acid ◽

Tyrosine Kinases ◽

Protein Tyrosine Phosphatases ◽

Sh2 Domain ◽

Tyrosine Phosphatases ◽

Protein Tyrosine ◽

Sh2 Domains

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Evolution of SH2 domains and phosphotyrosine signalling networks

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2012.0107 ◽

2012 ◽

Vol 367 (1602) ◽

pp. 2556-2573 ◽

Cited By ~ 49

Author(s):

Bernard A. Liu ◽

Piers D. Nash

Keyword(s):

Protein Interaction ◽

Tyrosine Kinases ◽

Protein Tyrosine Phosphatases ◽

Sh2 Domain ◽

Cellular Systems ◽

Specific Gene ◽

Interaction Domain ◽

Tissue Specific ◽

Protein Tyrosine ◽

Sh2 Domains

Src homology 2 (SH2) domains mediate selective protein–protein interactions with tyrosine phosphorylated proteins, and in doing so define specificity of phosphotyrosine (pTyr) signalling networks. SH2 domains and protein-tyrosine phosphatases expand alongside protein-tyrosine kinases (PTKs) to coordinate cellular and organismal complexity in the evolution of the unikont branch of the eukaryotes. Examination of conserved families of PTKs and SH2 domain proteins provides fiduciary marks that trace the evolutionary landscape for the development of complex cellular systems in the proto-metazoan and metazoan lineages. The evolutionary provenance of conserved SH2 and PTK families reveals the mechanisms by which diversity is achieved through adaptations in tissue-specific gene transcription, altered ligand binding, insertions of linear motifs and the gain or loss of domains following gene duplication. We discuss mechanisms by which pTyr-mediated signalling networks evolve through the development of novel and expanded families of SH2 domain proteins and the elaboration of connections between pTyr-signalling proteins. These changes underlie the variety of general and specific signalling networks that give rise to tissue-specific functions and increasingly complex developmental programmes. Examination of SH2 domains from an evolutionary perspective provides insight into the process by which evolutionary expansion and modification of molecular protein interaction domain proteins permits the development of novel protein-interaction networks and accommodates adaptation of signalling networks.

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Abstract 141: Deletion of Ptpn11 (Shp2) in Cardiomyocytes Leads to Dilated Cardiomyopathy

Circulation ◽

10.1161/circ.116.suppl_16.ii_5-d ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Maria I Kontaridis ◽

Wentien Yang ◽

Kendra Bence ◽

Darragh Cullen ◽

Bo Wang ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Tyrosine Kinases ◽

Mapk Pathway ◽

Genetic Diseases ◽

Critical Role ◽

Pressure Overload ◽

Protein Tyrosine Phosphatases ◽

Sh2 Domain ◽

Protein Tyrosine ◽

Erk Mapk

Heart failure is the leading cause of death in the U.S. Delineating the pathways that regulate cardiomyocyte function is essential to understanding the pathogenesis of cardiac disease. Many cardiomyocyte signaling pathways activate protein tyrosine kinases, yet the role of protein tyrosine phosphatases (PTPs) in the heart is unknown. Here, we show that mice with cardiac-specific deletion of Ptpn11 , the gene encoding the SH2 domain-containing PTP Shp2, rapidly develop a compensated dilated cardiomyopathy without an intervening hypertrophic phase. Primary Shp2 deficient cardiomyocytes are defective in Erk/MAPK activation in response to a variety of soluble agonists and pressure overload. Our results identify Shp2 as the first PTP known to have a critical role in cardiac function, suggest that Shp2’s cardio-protective role is mediated via control of the Erk/MAPK pathway, and have important implications for the pathogenesis of cardiac defects in the human genetic diseases Noonan Syndrome and LEOPARD Syndrome, which are caused by PTPN11 mutations.

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