Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways

Tong, Wei; Zhang, Jing; Lodish, Harvey F.

doi:10.1182/blood-2004-10-4093

Cited by 190 publications

(207 citation statements)

References 29 publications

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“…According to the previously identified functions of Lnk in other cell types, we hypothesized that Lnk may either promote or inhibit EC activation (14,16,23,24). Therefore, we first sought to determine whether Lnk expression was able to induce E-selectin and VCAM-1 expression on quiescent ECs, a typical feature of EC activation in response to proinflammatory cytokines, including TNF␣ and interleukin-1␤ (2, 10).…”

Section: Resultsmentioning

confidence: 99%

“…Overexpression of Lnk in the primary culture of the AGM region at embryonic day 11.5 suppressed the emergence of CD45 ϩ hematopoietic cells (18). Among mice nullizygous for the Lnk family members Lnk, APS, and SH2-B, Lnk-deficient mice exhibit the most profound alteration in hematopoiesis, including abnormal expansion of immature B cells (15), enhanced bone marrow repopulating activity (16), and elevated numbers of megakaryocytes (23) and erythroid progenitors (24). Taken together, these data suggest that Lnk may be a key player in EC differentiation, activation, and dysfunction.…”

Section: Discussionmentioning

confidence: 99%

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The Adaptor Molecule Lnk Negatively Regulates Tumor Necrosis Factor-α-dependent VCAM-1 Expression in Endothelial Cells through Inhibition of the ERK1 and -2 Pathways

Fitau¹,

Boulday²,

Coulon³

et al. 2006

Journal of Biological Chemistry

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Lnk, with APS and SH2-B (Src homology 2-B), belongs to a family of SH2-containing proteins with potential adaptor functions. Lnk regulates growth factor and cytokine receptor-mediated pathways implicated in lymphoid, myeloid, and platelet homeostasis. We have previously shown that Lnk is expressed and up-regulated in vascular endothelial cells (ECs) in response to tumor necrosis factor-␣ (TNF␣). In this study, we have shown that, in ECs, Lnk down-regulates the expression, at both mRNA and protein levels, of the proinflammatory molecules VCAM-1 and E-selectin induced by TNF␣. Mechanistically, our data indicated that, in response to TNF␣, NFB/p65 phosphorylation and translocation as well as IB␣ phosphorylation and degradation were unchanged, suggesting that Lnk does not modulate NFB activity. However, Lnk activates phosphatidylinositol 3-kinase (PI3K) as reflected by Akt phosphorylation. Our results identify endothelial nitric-oxide synthase as a downstream target of Lnk-mediated activation of the PI3K/Akt pathway and HO-1 as a new substrate of Akt. We found that sustained Lnkmediated activation of PI3K in TNF␣-activated ECs correlated with the inhibition of ERK1/2 phosphorylation, whereas phosphorylation of p38 and c-Jun NH 2 -terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) was unchanged. ERK1/2 inhibition decreases VCAM-1 expression in TNF␣-treated ECs. Collectively, our results identify the adaptor Lnk as a negative regulator in the TNF␣-signaling pathway mediating ERK inhibition and suggest a role for Lnk in the interplay between PI3K and ERK triggered by TNF␣ in ECs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Adaptor Molecule Lnk Negatively Regulates Tumor Necrosis Factor-α-dependent VCAM-1 Expression in Endothelial Cells through Inhibition of the ERK1 and -2 Pathways

Fitau¹,

Boulday²,

Coulon³

et al. 2006

Journal of Biological Chemistry

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“…LNK is a negative regulator of thrombopoietinFthrombopoietin receptor (MPL)-mediated JAK2 activation; LNK-deficient mice exhibit increased number of megakaryocytes with increased ploidy, 5 increased number of erythrocyte progenitors, 6 as well as an expanded hematopoietic stem cell pool with enhanced self renewal. 7 LNK has been shown to down regulate signaling downstream of MPLW515L and JAK2V617F in vitro.…”

Section: Introductionmentioning

confidence: 99%

LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations

et al. 2010

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LNK mutation analysis was performed in 61 patients with blast-phase myeloproliferative neoplasms (MPN); post-primary myelofibrosis (PMF) in 41, post-polycythemia vera in 11 and post-essential thrombocythemia in 9 patients. Paired chronicblast phase sample analysis was possible in 26 cases. Nine novel heterozygous LNK mutations were identified in eight (13%) patients: six exon 2 missense mutations involving codons 215, 220, 223, 229 and 234, a synonymous mutation involving codon 208, and two deletion mutations involving exon 2 (685-691_delGGCCCCG) or exon 5 (955_delA); eight affected the pleckstrin homology (PH) domain. Mutations were detected in six (9.8%) blast-phase samples; chronic-phase sample analysis in four of these revealed the same mutation in one. Mutant LNK was detected in chronic-phase only in two patients and in both chronic-blast phases in one. JAK2V617F was documented in three and IDH2R140Q in one LNK-mutated patients. LNK mutations were not detected in 78 additional patients with chronic-phase MPN enriched for TET2, IDH, JAK2V617F, or MPL-mutated cases. We conclude that LNK mutations (i) target an exon 2 'hot spot' in the PH domain spanning residues E208-D234, (ii) might be more prevalent in blast-phase PMF and (iii) are not mutually exclusive of other MPN-associated mutations but rarely occur in their presence in chronic-phase disease.

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“…92 The SH2 and PH (pleckstrin homology domain) adapter protein Lnk was shown to not only bind to phosphorylated tyrosine residues of both TpoR and EpoR but also to exert a negative role on signaling by these receptors. 93,94 It is not known whether the defects in this negative regulatory mechanism are operating in MPNs.…”

Section: Tpor and Mpnsmentioning

confidence: 99%

Aberrant signal transduction pathways in myeloproliferative neoplasms

2008

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The BCR-ABL-negative myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), entered the spotlight in 2005 when the unique somatic acquired JAK2 V617F mutation was described in 495% of PV and in 50% of ET and PMF patients. For the very rare PV patients who do not harbor the JAK2 V617F mutation, exon 12 JAK2 mutants were discovered also to result in activated forms of JAK2. A minority of ET and PMF patients harbor mutations that constitutively activate the thrombopoietin receptor (TpoR). In bone marrow reconstitution models based on retroviral transduction, the phenotype induced by JAK2 V617F is less severe and different from the rapid fatal myelofibrosis induced by TpoR W515L. The reasons for these differences are unknown. Exactly by which mechanism(s) one acquired somatic mutation, JAK2 V617F, can promote three different diseases remains a mystery, although gene dosage and host genetic variation might have important functions. We review the recent progress made in deciphering signaling anomalies in PV, ET and PMF, with an emphasis on the relationship between JAK2 V617F and cytokine receptor signaling and on cross-talk with several other signaling pathways.

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Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways

Cited by 190 publications

References 29 publications

The Adaptor Molecule Lnk Negatively Regulates Tumor Necrosis Factor-α-dependent VCAM-1 Expression in Endothelial Cells through Inhibition of the ERK1 and -2 Pathways

The Adaptor Molecule Lnk Negatively Regulates Tumor Necrosis Factor-α-dependent VCAM-1 Expression in Endothelial Cells through Inhibition of the ERK1 and -2 Pathways

LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations

Aberrant signal transduction pathways in myeloproliferative neoplasms

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