Oncogenic CBL Mutants Have Transforming Potential in Cells Expressing the FLT3 Tyrosine Kinase.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1446-1446
Author(s):  
Carola Reindl ◽  
Sridhar Vempati ◽  
Hilmar Quentmeier ◽  
Gudrun Mellert ◽  
Wolfgang Hiddemann ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Deletion Mutant ◽  
Ring Finger ◽  
Dominant Negative ◽  
Leukemic Cells ◽  
Regulatory Function ◽  
Lymphoid Leukemia ◽  
Acute Leukemias ◽  
Downstream Signaling

Abstract CBL is a E3-ubiquitin ligase, that negatively regulates many receptor tyrosine kinases (RTKs). Translocations (t(4;11); t(11;14) involving CBL in humans and two oncogenic CBL deletion mutants, CBL-70Z and v-CBL, inducing B-cell lymphomas in mice, were described. The RTK Fms-like tyrosine kinase 3 (FLT3) is expressed by the leukemic cells of 70–90% of patients with acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) and is highly implicated in the malignant transformation by harbouring activating mutations, aberrant autocrine stimulation or overexpression. We hypothesized that CBL could play a role in regulating FLT3 activity and if mutated, could cause aberrant FLT3 signaling in hematopoietic cells. To analyze if CBL mutants could lead to transformation of FLT3-expressing cells we stably transduced Ba/F3 cells with CBL-WT, CBL-70Z or v-CBL alone or together with FLT3-WT. Coexpression of FLT3-WT and a CBL mutant, CBL-70Z or v-CBL, but not CBL-WT or expression of a CBL-construct alone, conferred IL-3 independent growth to Ba/F3 cells. In presence of FLT3 ligand FLT3-WT/CBLmutant-expressing cells showed hyperproliferation. To determine whether the proliferative advantage of FLT3-WT/CBL-70Z and FLT3-WT/v-CBL cells is mediated by FLT3 we cultivated the cells in presence of selective FLT3 inhibitors, SU5614 and PKC412. Both inhibitors were able to abrogate the IL-3 independent and FL-stimulated growth of FLT3-WT/CBL-70Z and FLT3-WT/v-CBL cells. The FLT3-WT receptors and the downstream signaling pathway, STAT5, were constitutively active in FLT3-WT/CBLmutant-expressing cells in contrast to control cells. To clarify the mechanism of transformation we performed internalization assays. The rate and speed of internalization of the FLT3-WT receptors were not altered in FLT3-WT/CBL-70Z and FLT3-WT/v-CBL cells compared to FLT3-WT cells. However, we could show that CBL-WT promotes FLT3 degradation. To investigate if CBL mutations play a role in acute leukemias we screened the cDNA of 62 AML and 6 ALL cell lines and found a CBL deletion mutant in MOLM-13 and MOLM-14 cells lacking exon 8, which comprises parts of the linker and RING finger domain. Hence, this mutation targets the same functionally important regions of the CBL protein than the CBL-70Z deletion. In summary, CBL-70Z and v-CBL, but not CBL-WT, confer a transforming potential to cells expressing FLT3. The pro-proliferative phenotype of FLT3-WT/CBL-70Z and FLT3-WT/v-CBL cells is mediated by an increase in FLT3 tyrosine kinase activity. The CBL-70Z and v-CBL mutations were hypothesized to act in a dominant negative manner abrogating the negativ-regulatory function of CBL-WT. We identified a CBL deletion mutant in the MOLM-13 and MOLM-14 cells, that is reminiscent of CBL-70Z, indicating that CBL mutations might play a role in the pathogenesis of acute leukemias.

New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases

Blood ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 2429-2437 ◽  
Author(s):  
Federica Toffalini ◽  
Jean-Baptiste Demoulin
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Cell Transformation ◽  
Chromosomal Rearrangements ◽  
Point Mutations ◽  
Large Cell ◽  
Kinase Domain ◽  
Leukemic Cells

Abstract A large number of alterations in genes encoding receptor tyrosine kinase (RTK), namely FLT3, c-KIT, platelet-derived growth factor (PDGF) receptors, fibroblast growth factor (FGF) receptors, and the anaplastic large cell lymphoma kinase (ALK), have been found in hematopoietic malignancies. They have drawn much attention after the development of tyrosine kinase inhibitors. RTK gene alterations include point mutations and gene fusions that result from chromosomal rearrangements. In both cases, they activate the kinase domain in the absence of ligand, producing a permanent signal for cell proliferation. Recently, this simple model has been refined. First, by contrast to wild-type RTK, many mutated RTK do not seem to signal from the plasma membrane, but from various locations inside the cell. Second, their signal transduction properties are altered: the pathways that are crucial for cell transformation, such as signal transducer and activator of transcription (STAT) factors, do not necessarily contribute to the physiologic functions of these receptors. Finally, different mechanisms prevent the termination of the signal, which normally occurs through receptor ubiquitination and degradation. Several mutations inactivating CBL, a key RTK E3 ubiquitin ligase, have been recently described. In this review, we discuss the possible links among RTK trafficking, signaling, and degradation in leukemic cells.

Regulatory Role of the Sprouty Gene Family on PDGFβR Fusion Oncogenes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3509-3509
Author(s):  
Silja D. Andradottir ◽  
Magnus K. Magnusson
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Gene Family ◽  
Cell Lines ◽  
Tyrosine Kinases ◽  
Regulatory Genes ◽  
Dominant Negative ◽  
Regulatory Role ◽  
Thymidine Uptake

Abstract Constitutively activated fusion tyrosine kinases of the Platelet-dervied growth factor β receptor (PDGFβR) family have been described in patients with chronic myelomonocytic leukemia (CMML). Like other tyrosine kinase driven myeloproliferative syndromes, CMML is characterized by progression leading to highly aggressive acute leukemia. In order to understand the progression of these malignancies we are studying tyrosine kinase pathway regulatory genes. In this study we focus on the functional role of the sprouty gene family in the regulation of PDGFβR fusion oncogenes. Sprouty (Spry) has recently been identified as a repressor of receptor tyrosine kinases signaling in vertebrates and invertebrates. The studies of sprouty in the mammalian system have thus far mostly focused on the regulation of the epidermal and fibroblast growth factor receptor, while nothing is known about the possible regulation of PDGF receptors by sprouty proteins and nothing is known about regulation of mutationally activated tyrosine kinases. Expression plasmids containing human sprouty wildtype genes (Spry1-3 WT) were constructed, along with a series of plasmids containing dominant negative variants by site-direct mutagenesis in critically conserved domains [Spry1(Y53F), Spry2(Y55F), Spry3(Y27F)]. Stable cell lines containing these plasmids have been generated in the BaF3 background with or without the constitutively activated Rabaptin-5/PDGFβR (R/P) fusion oncoprotein. Effects on cell growth and downstream signaling events were studied. Spry1 WT and Spry3 WT signifcantly inhibit growth of R/P transformed BaF3 cell lines. This inhibition was much more pronounced in IL3 depleted media indicating that the inhibition is mediated through PDGFβR tyrosine kinase inhibition. The dominant negative forms, Spry1(Y53F) and Spry3(Y27F) stimulated growth of the the same BaF3 cell lines. Results from [3H]thymidine uptake studies in these cell lines showed decreased uptake in Spry1 WT and Spry3 WT transduced cells and increased uptake in the dominant negative forms, indicating that the effects are through increased proliferation rather than decreased apoptosis. Interestingly, R/P transformed BaF3 cell lines transfected with plasmid containing Spry2 WT and Spry2(Y55F) showed inverse results, Spry2 WT stimulated growth while Spry2(Y55F) inhibited growth. A possible explanation for stimulatory effects of Spry2 is that this Spry variant contains a Cbl binding domain previously shown to prevent Cbl mediated ubiquitylation and degradation of RTKs. We are currently studying the downstream targets of the Spry regulation of PDGFβR focusing on Ras and MAPkinase pathways. In conclusion, we have shown that Spry1 and Spry3 inhibits growth of PDGFβR transformed BaF3 cell lines, while Spry2 stimulates growth. This is the first evidence for regulatory role of Sprouty genes in activated fusion tyrosine kinase. This conserved family of tyrosine kinase regulatory genes is an ideal target for studies of disease progression in tyrosine kinase driven malignancies.

Leukemogenic Cascade Induced by a Constitutively Active Neurotrophin Receptor, ΔTrkA.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1442-1442
Author(s):  
Zhixiong Li ◽  
Johann Meyer ◽  
Mathias Rhein ◽  
Olga Kustikova ◽  
Cornelia Rudolph ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinases ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Insertion Site ◽  
Leukemic Cells ◽  
Neurotrophin Receptor ◽  
Target Cells ◽  
Receptor Signaling ◽  
Lymphoid Leukemia

Abstract Various neurotrophins (NT) are expressed in the hematopoietic microenvironment to deliver their signals through TRK receptor tyrosine kinases. Although previous reports suggested a transforming potential of activated TRK signaling in hematopoiesis, the target cells and underlying mechanisms are largely unknown. In this study, we investigated in vivo leukemogenesis of ΔTrkA, a mutant of TRKA isolated from a patient with acute myeloid leukemia (AML). Retroviral expression of ΔTrkA in myeloid 32D cells induced AML at ~4 weeks after transplantation into syngeneic C3H/Hej mice (n=11). C57BL/6J mice (n=15) transplanted with ΔTrkA-transduced primary bone marrow cells developed myeloid and/or lymphoid leukemia with infiltration in multiple organs including bone marrow, spleen, liver, lung, and central nervous system. While activation of a tyrosine kinase generally is not sufficient to cause AML, surprisingly, 7 out of 15 C57BL/6J mice developed a polyclonal AML with a latency of <12 days. This strongly suggests that ΔTrkA is sufficient to block differentiation and promote proliferation of short-term repopulating myeloid progenitor cells. This simultaneous interference with two complementary leukemogenic pathways has not been reported for other oncogenic tyrosine kinases. However, as half of the mice survived this disorder, ΔTrkA does not seem to confer self-renewal properties to transformed blasts. Supporting this hypothesis, transplantation into lethally irradiated secondary recipients did not re-induce polyclonal AML, but rather gave rise to clonal acute lymphoblastic leukemia (ALL) after a latency of >78 days. This suggests that ΔTrkA can also transform long-term repopulating cells with a lymphoid potential. Retroviral insertion site analyses and spectral karyotyping revealed that induction of ALL by ΔTrkA required additional genetic lesions: Leukemic cells showed retroviral insertions in proto-oncogenes Bcl11a and Bcl11b, among others. Characterization of signal transduction demonstrated that PI3K and mTOR-raptor were crucial components of the transforming pathway induced by ΔTrkA. Phospholipase D was an important contributing factor, whereas STAT and MAP kinase pathways were not involved. In summary, our findings reveal potent transforming properties of altered NT receptor signaling in leukemia induction, which are in many respects distinct from other oncogenic tyrosine kinases. We would suggest to further evaluate the role of NT receptor signaling in leukemia pathogenesis, prognosis and treatment.

scholarly journals Essential diurnal Rac1 activation during retinal phagocytosis requires αvβ5 integrin but not tyrosine kinases focal adhesion kinase or Mer tyrosine kinase

2012 ◽  
Vol 23 (6) ◽  
pp. 1104-1114 ◽  
Author(s):  
Yingyu Mao ◽  
Silvia C. Finnemann
Keyword(s):  
Tyrosine Kinase ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Tyrosine Kinases ◽  
Rho Gtpases ◽  
Milk Fat ◽  
Retinal Pigment ◽  
Dominant Negative ◽  
Rpe Cells ◽  
Mer Tyrosine Kinase

Diurnal phagocytosis of shed photoreceptor outer-segment particles by retinal pigment epithelial (RPE) cells belongs to a group of conserved clearance mechanisms employing αv integrins upstream of tyrosine kinases and Rho GTPases. In this study, we tested the interdependence of the tyrosine kinases focal adhesion kinase (FAK) and Mer tyrosine kinase (MerTK) and Rho GTPases during engulfment. RPE cells activated and redistributed Rac1, but not RhoA or Cdc42, during phagocytosis. Toxin B, overexpression of dominant-negative Rac1, or decreasing Rac1 expression prevented particle engulfment. Fluorescence microscopy showed that Rac1 inhibition had no obvious effect on F-actin arrangement in resting RPE but prevented recruitment of F-actin to surface-bound phagocytic particles. Quantification of active GTP-Rac1 in wild-type and mutant RPE in culture and in vivo revealed that Rac1 activation during phagocytosis requires αvβ5 integrin and its ligand milk fat globule EGF factor-8 (MFG-E8) but not the receptor tyrosine kinase MerTK. Abolishing tyrosine kinase signaling downstream of αvβ5 toward MerTK by inhibiting FAK specifically or tyrosine kinases generally neither prevented Rac1 activation nor F-actin recruitment during phagocytosis. Likewise, inhibiting Rac1 had no effect on FAK or MerTK activation. We conclude that MerTK activation via FAK and F-actin recruitment via Rac1 both require MFG-E8–ligated αvβ5 integrin. Both pathways are independently activated and required for clearance phagocytosis.

scholarly journals Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 1022-1024 ◽  
Author(s):  
Michael A. Caligiuri ◽  
Roger Briesewitz ◽  
Jianhua Yu ◽  
Lisheng Wang ◽  
Min Wei ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Ubiquitin Ligase ◽  
Tyrosine Kinases ◽  
Rna Splicing ◽  
Myeloid Leukemia ◽  
Ring Finger ◽  
Missense Mutations ◽  
Acute Leukemias ◽  
Protein Levels ◽  
Acute Myeloid

Abstract The CBL ubiquitin ligase targets a variety of activated tyrosine kinases (TKs) for degradation. Many TKs are mutationally or autocrine activated and/or often overexpressed at the mRNA and protein levels in acute leukemias. We hypothesized that CBL is mutated in patients with acute myeloid leukemia (AML). Four of 12 patients and the MOLM-13 cell line harbored c-CBL mutations, either RNA splicing mutations, missense mutations, or a nucleotide insertion. Additionally, 1 of the 12 patients harbored a missense mutation in the related CBL-b gene. Each c-CBL mutation involves the structurally important α-helix within the linker region, while the mutation in CBL-b was located in the Ub-E2 protein-binding RING finger. Short-interfering RNA knockdown of mutant c-CBL present in MOLM-13 cells was growth inhibitory. In summary, novel mutations in c-CBL and CBL-b have been identified in human AML and may represent potential targets for novel therapeutics.

scholarly journals Phage-Displayed Peptides for Targeting Tyrosine Kinase Membrane Receptors in Cancer Therapy

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 649
Author(s):  
Annamaria Aloisio ◽  
Nancy Nisticò ◽  
Selena Mimmi ◽  
Domenico Maisano ◽  
Eleonora Vecchio ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Phage Display ◽  
Tyrosine Kinases ◽  
Peptide Ligands ◽  
Membrane Receptors ◽  
Downstream Signaling ◽  
Cancer Pathogenesis

Receptor tyrosine kinases (RTKs) regulate critical physiological processes, such as cell growth, survival, motility, and metabolism. Abnormal activation of RTKs and relative downstream signaling is implicated in cancer pathogenesis. Phage display allows the rapid selection of peptide ligands of membrane receptors. These peptides can target in vitro and in vivo tumor cells and represent a novel therapeutic approach for cancer therapy. Further, they are more convenient compared to antibodies, being less expensive and non-immunogenic. In this review, we describe the state-of-the-art of phage display for development of peptide ligands of tyrosine kinase membrane receptors and discuss their potential applications for tumor-targeted therapy.

Phosphorylation of Receptor Tyrosine Kinase ROR1 At Tyrosine 641, 646 and Serine 652 residues Might Be of Importance for the Survival of CLL Leukemic Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3885-3885
Author(s):  
Mohammad Hojjat-Farsangi ◽  
Amir Hossein Daneshmanesh ◽  
Martin Norin ◽  
Åsa Sandin ◽  
Abdul Salam Khan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Tyrosine Kinase ◽  
Western Blot ◽  
Tyrosine Kinases ◽  
Conflicts Of Interest ◽  
Annexin V ◽  
Kinase Domain ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Tyrosine Kinase Domain

Abstract Abstract 3885 Background: Receptor tyrosine kinases (RTK) play crucial roles for different normal cellular processes as cell proliferation/differentiation, apoptosis and survival, as well as for the malignant phenotype of many types of cancer. ROR1, as a member of twenty RTKs families, has important functions during normal embryogenesis. ROR1 has shown to be overexpressed in chronic lymphocytic leukemia (CLL), mantle cell lymphoma and other hematological malignancies, as well as in solid tumors. ROR1 inhibition in CLL cells and cell lines with high expression of ROR1 induced specific apoptosis of the cells. In this study, we investigated the effects of an anti-ROR1 mAb against the extracellular CRD domain for specific dephosphorylation at the tyrosine kinase domain of ROR1 in CLL cells. The CRD domain contains a frizzle receptor, which is considered to be the ligand-binding region for e.g. Wnt5a. Wnt5a has been suggested to stimulate growth of CLL cells. Aims: To investigate phosphorylation of tyrosine and serine residues, within the tyrosine kinase domain of ROR1, of importance for survival of CLL cells. Methods: Bioinformatic analysis of the ROR1 structure revealed that three amino acid residues in the tyrosine kinase domain might be critically phosphorylated. Based on this prediction, a 19 amino acid long peptide, phosphorylated at two tyrosine (tyrosine 641, 646) and one serine (serine 652) residues was designed and used for immunization of rabbits. An anti-phospho-ROR1 (pROR1) polyclonal antibody (pAb) with high titers of anti-pROR1 pAb was purified, using phospho-peptide affinity chromatography. The specificity of anti-pROR1 pAb was determined by ELISA, immunoprecipitation (IP) and western blot experiments. An anti-ROR1 mAb (IgG) (CRD 1D8 clone) was used to analyse the effects on ROR1 phosphorylation in CLL cells at tyrosine 641, 646 and serine 652 residues preceding apoptosis. ROR1 phosphorylation was investigated by western blot and IP of ROR1 probed with anti-pROR1 pAb, from untreated and CLL cells treated with the anti-CRD 1D8 mAb. Quantitative intracellular staining of ROR1 by flowcytometry in time kinetics experiment after treatment with anti-CRD 1D8 mAb was also used to check phosphorylation of ROR1. Annexin V/PI staining (flowcytometry), MTT assay, PARP and caspase 8 cleavage as well as MCL-1 protein (western blot) were used for detection of apoptosis. To investigate phosphorylation and localization of 64–130 kDa ROR1 isoforms in various compartments of CLL cells, lysates were prepared from the nucleus and cytoplasmic proteins of CLL cells. Results: Two tyrosine (641, 646) residues and one serine (652) residue of the tyrosine kinase domain were phosphorylated in CLL cells. As previously described (Mellstedt et al, Abstract No: 1771, 53th ASH annals meeting, 2011), the 64, 105 and 130 kDa ROR1 isoforms were shown to be constitutively phosphorylated at tyrosine and serine residues in CLL leukemic cells. Treatment of CLL cells with an anti-ROR1 mAb against the CRD domain induced rapid dephosphorylation of ROR1 at tyrosine 641, 646 and serine 652 residues within 20 min and gradually increased up to 4 hours. The phosphorylated 64 kDa ROR1 isoform was localized to the nucleus of CLL cells and probably represents an intracellular part of ROR1, while the ROR1 130 kDa isoform was presented both in cytoplasm and nucleus of CLL cells. Conclusion: Our data show that the ROR1 molecule is phosphorylated at tyrosine 641, 646 and serine 652 residues. The presence of 64 and 130 kDa ROR1 isoforms in the nucleus of CLL cells may suggest a role of these isoforms as transcription factors. Collectively, the data might suggest that phosphorylated ROR1 may be an important protein for the growth of CLL cells as well as an interesting structure to target in a therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Inhibition of Src tyrosine kinase stimulates adrenal androgen production

2003 ◽  
Vol 30 (3) ◽  
pp. 287-299 ◽  
Author(s):  
R Sirianni ◽  
BR Carr ◽  
S Ando ◽  
WE Rainey
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Dominant Negative ◽  
Mrna Levels ◽  
Adrenal Androgen ◽  
Adrenal Androgens ◽  
Src Tyrosine Kinase ◽  
Adrenal Cell ◽  
Adrenal Cells ◽  
Steroidogenic Acute Regulatory

A unique characteristic of the primate adrenal is the ability to produce 19-carbon steroids, often called the adrenal androgens. Although it is clear that the major human adrenal androgens, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S), are produced almost solely in the adrenal reticularis, the mechanisms regulating production are poorly understood. Herein, we tested the hypothesis that the Src family of tyrosine kinases are involved in the regulation of adrenal androgen production. The NCI-H295R human adrenal cell line and primary human adrenal cells in culture were used to study adrenal androgen production and expression of enzymes involved in steroidogenesis. To examine the role of Src tyrosine kinase, cells were treated with PP2, a specific Src inhibitor. Alternatively, adrenal cells were transfected with an expression vector containing a dominant-negative form of Src. PP2 treatment inhibited basal cortisol production while significantly increasing the production of DHEA and DHEA-S (together referred to as DHEA(S)) in both adrenal cell models. The effect of PP2 on steroidogenesis occurred along with a rapid induction of steroidogenic acute regulatory (StAR) protein synthesis as revealed by Western analysis. Treatment with PP2 also increased mRNA levels for StAR, and cholesterol side-chain cleavage (CYP11A) and 17alpha-hydroxylase/17,20-lyase (CYP17) enzymes. Treatment of adrenal cells with the cAMP agonist dibutyryladenosine cyclic monophosphate (dbcAMP), stimulated the production of cortisol and DHEA(S). However, treatment of adrenal cells with a combination of PP2 and dbcAMP enhanced the production of DHEA(S) while inhibiting cortisol production. During dbcAMP treatment PP2 was able to augment the expression of CYP17 and to inhibit the induction of 3beta-hydroxysteroid dehydrogenase type 2 (HSD3B2) levels. Increasing the CYP17 to HSD3B2 ratio is likely to promote the use of steroid precursors for the production of DHEA(S) and not for cortisol. Taken together these data suggest that the inhibition of Src tyrosine kinases causes adrenal cells to adopt a reticularis phenotype both by the production of DHEA(S) and by the steroidogenic enzymes expressed.

scholarly journals Structure, Function, and Regulation of the SRMS Tyrosine Kinase

2020 ◽  
Vol 21 (12) ◽  
pp. 4233 ◽  
Author(s):  
Chakia J. McClendon ◽  
W. Todd Miller
Keyword(s):  
Tyrosine Kinase ◽  
Cell Signaling ◽  
Structure Function ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Structural Model ◽  
Downstream Signaling ◽  
Current State ◽  
Cancer Cell Signaling ◽  
Nonreceptor Tyrosine Kinases

Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (SRMS) is a tyrosine kinase that was discovered in 1994. It is a member of a family of nonreceptor tyrosine kinases that also includes Brk (PTK6) and Frk. Compared with other tyrosine kinases, there is relatively little information about the structure, function, and regulation of SRMS. In this review, we summarize the current state of knowledge regarding SRMS, including recent results aimed at identifying downstream signaling partners. We also present a structural model for the enzyme and discuss the potential involvement of SRMS in cancer cell signaling.

DISSEMINATED INTRAVASCULAR COAGULATION (DIC) AND ACUTE LEUKEMIA:IDENTIFICATION OF A NEW CELLULAR PROCOAGULANT

1987 ◽  
Author(s):  
A Falang ◽  
G M Alessio ◽  
M Donati ◽  
T A Barbui
Keyword(s):  
Proteinase Inhibitors ◽  
Cysteine Proteinase ◽  
Vitamin K Antagonists ◽  
Control Cell ◽  
Leukemic Cells ◽  
Lymphoid Leukemia ◽  
Acute Leukemias ◽  
Cell Extracts ◽  
Therapeutic Tools ◽  
Set Up

There is an enhanced incidence (>50%) of severe coagulopathy in association with several types of acute leukemias. Cell associated procoagulants are considered important in this context. So far only a Tissue Factor (TF)-type procoagulant has been described in leukemic cells. We have set up here the experimentalconditions to identify other possible cellular procoagulants in leukemia. We have tested blast cell extracts from 21 patients with 5 different cytological subtypes (from Ml to M5 of acute non lymphoid leukemia (ANLL), according to theFAB classification, in order to assay whether they express "cancer procoagulant" (CP), a F VH-independent FX activating cysteine proteinase (Falanga … Gordon, 1985; Donati, et al. 1986). All the samples shortened the recalcification time of normal human plasma, the effect being significantly greater (p<0.001) in the M3 group. The activity was 20% to 100% independent from the presence of FVII and was susceptible to 2 cysteine proteinase inhibitors (Iodoacetamide, 2 mM, and HgCl2 ,0.1 mM) in all of the extracts but the M5 type. In addition, M2 and M3 samples directly activated pure FX in a two stage clotting assay. Control cell extracts from 10 healthy donors did not show any procoagulant activity, under the same conditions. This study provides evidence for a new procoagulant expressed by cells of ANLL; the peculiar characteristics of this procoagulant (i.e. its confinement to the malignant phenotype, its shedding into the plasma, its possible modulation by vitamin K antagonists) make this observation of potential interest in the development of new diagnostic and therapeutic tools in ANLL.

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