Syk Is Required for BCR-mediated Activation of p90Rsk, but Not p70S6k, via a Mitogen-activated Protein Kinase-independent Pathway in B Cells

Li, Hsiu-Ling; Forman, Mark S.; Kurosaki, Tomohiro; Puré, Ellen

doi:10.1074/jbc.272.29.18200

Cited by 33 publications

(29 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Syk binds to ITAM and initiates signaling through the Ras, PI3-K and PLC-g signal pathways. 5,6 We showed the association between the p85 subunit of PI3-K and TEL-Syk fusion protein followed by the constitutive activation of Akt. Akt is the serine/threonine kinase and an important component of cell survival signaling.…”

Section: Discussionmentioning

confidence: 99%

“…It has two amino-terminal Src-homology 2 domains and a carboxy-terminal kinase domain, binds to the immunoreceptor tyrosine-based activation motif (ITAM) and initiates signaling through the Ras, phosphatidyl inositol 3 kinase (PI3-K) and phospholipase C-g (PLC-g) signal pathways. [3][4][5][6] Syk-deficient mice show a maturational block at the pro-B to pre-B cell transition. 7,8 Aberrant splicing and protein deficiency of Syk was found in childhood pro-B cell acute lymphoblastic leukemia (ALL).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways

et al. 2004

View full text Add to dashboard Cite

We previously reported the fusion of the TEL gene to the Syk gene in myelodysplastic syndrome with t(9;12)(q22;p12). TELSyk fusion transformed interleukin-3 (IL-3)-dependent murine hematopoietic cell line BaF3 to growth factor independence. Here, we investigate the intracellular signal transduction of the stable transfectants. TEL-Syk fusion protein was associated with the p85 subunit of phosphatidyl inositol 3 kinase (PI3-K) followed by the activation of Akt in the absence of IL-3. Vav, phospholipase C-c2 and mitogen-activated protein kinase (MAPK) were also constitutively activated. TEL-Syk also activated the signal transducer and activator of transcription 5 (STAT5) in the absence of Janus kinase 2 activation. None of these kinases were phosphorylated in the BaF3 cells transfected with TELDPNT-Syk in which the oligomerization domain of TEL was deleted. Inhibitor analysis showed that the MAPK pathway was important in TEL-Syk-mediated cell proliferation. The immunofluorescence technique revealed that the TEL-Syk fusion protein was located in the cytoplasm. These data suggest that TEL-Syk fusion protein in the cytoplasm leads to the constitutive activation of PI3-K/Akt, MAPK and STAT5 signal pathways, which are closely involved in IL-3-independent cell proliferation of BaF3 cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways

et al. 2004

View full text Add to dashboard Cite

show abstract

“…The Syk protein tyrosine kinase (PTK) along with Zap-70 protein tyrosine kinase comprise a family of cytoplasmic kinases that play important roles in signal transduction pathways activated by the engagement of hematopoietic cell surface receptors (Gulbins et al, 1994;Sieh et al, 1994;Takata et al, 1994;Bolen, 1995;Kurosaki et al, 1995;Nagai et al, 1995;Sidorenko et al, 1995;Chan and Shaw, 1996;Deckert et al, 1996;Latour et al, 1996;Law et al, 1996;Panchamoorthy et al, 1996;Takata and Kurosaki, 1996;Bolen and Brugge, 1997;Harmer and DeFranco, 1997;Li et al, 1997;Qin et al, 1998). SYK also plays a pivotal role in B-cell development (Cheng et al, 1995;Turner et al, 1997;Cornall et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Hypermethylation of the spleen tyrosine kinase promoter in T-lineage acute lymphoblastic leukemia

et al. 2003

View full text Add to dashboard Cite

Sequence analysis of the noncoding first exon (exon 1) of the Syk gene demonstrated the presence of a previously cloned CpG island (GenBank #Z 65706). Transient transfection analysis in Daudi cells demonstrated promoter activity (18-fold increase over parental luciferase plasmid) for a 348 bp BstXI-BsrBI fragment containing this island. This region exhibits a high GC content (B75%), contains several SP1 binding sites and a potential initiator sequence, but lacks a strong TATA consensus. Bisulfite sequencing and methylation-specific PCR (MSP) of this region demonstrated that the Syk promoter CpG island was largely unmethylated in Blineage leukemia cell lines, control peripheral blood cells, human thymocytes and CD3 + T lymphocytes. However, dense methylation was seen in four T-lineage leukemia cell lines, Jurkat, H9, Molt 3 and HUT 78. MSP screening of leukemia cells from six T-lineage acute lymphoblastic leukemia (ALL) patients demonstrated methylation of the Syk promoter CpG island in one T-lineage ALL patient. Promoter methylation was correlated with reduced to absent expression of Syk mRNA and SYK protein in the T-lineage leukemia cell lines. Treatment of the leukemia lines Ha and Molt 3, with the methylation inhibitor, 5-aza-2 0 -deoxycytidine (5-aza-CdR) resulted in increased Syk mRNA expression. The presence of a methylated promoter sequence in these T-lineage leukemia cell lines and in one T-lineage patient suggests a potential role for SYK as a tumor suppressor in T-ALL.

show abstract

“…Phosphorylation at Y352 is considered sufficient to increase Syk activity enough to phosphorylate certain downstream substrates and trans-autophosphorylate tyrosines 525 and 526 in the activation loop. [19][20][21][22][23] The function of the tyrosines in the activation loop has still not been completely resolved, but most studies indicate that their phosphorylation is required to fully convert or stabilize Syk in an active conformation. 22,23 Once activated, Syk propagates the BCR signal by associating with adaptor proteins and phosphorylating important signaling intermediates, including B-cell linker protein (BLNK), PI3K (phosphatidylinositol 3-kinase) and PLCg2 (phospholipase Cg2).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells

et al. 2008

View full text Add to dashboard Cite

The protein kinase Syk is a key mediator of proximal B-cell receptor (BCR) signaling. Following antigen stimulation, Syk is recruited to the BCR and becomes activated by phosphorylation at Y352. Recently, Syk was found to be constitutively phosphorylated in several common B-cell lymphoma subtypes, indicating a role for antigen-independent Syk activation in the pathogenesis of these diseases. We now report that Syk is constitutively phosphorylated on the activating Y352 residue in chronic lymphocytic leukemia (CLL) B cells. To examine the effects of constitutive Syk activity on intracellular signaling and leukemic cell survival, we performed in vitro studies with the Syk inhibitor R406. Treatment with R406 induced leukemic cell apoptosis in the majority of investigated cases and affected the basal activity or expression of several pro-survival molecules regulated by Syk, including the Akt and extracellular signalregulated (ERK) kinases, and the anti-apoptotic protein Mcl-1. In addition, R406 prevented the increase in leukemic cell viability induced by sustained BCR engagement and inhibited BCR-induced Akt activation and Mcl-1 upregulation. Collectively, these data identify Syk as a potential target for CLL treatment and suggest that inhibition of this kinase could provide a double therapeutic benefit by disrupting both antigen-dependent and antigen-independent signaling pathways that regulate leukemic cell survival.

show abstract

Syk Is Required for BCR-mediated Activation of p90Rsk, but Not p70S6k, via a Mitogen-activated Protein Kinase-independent Pathway in B Cells

Cited by 33 publications

References 69 publications

TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways

TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways

Hypermethylation of the spleen tyrosine kinase promoter in T-lineage acute lymphoblastic leukemia

Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells

Contact Info

Product

Resources

About