Adaptor protein Lnk negatively regulates the mutant MPL, MPLW515L associated with myeloproliferative disorders

Gery, Sigal; Gueller, Saskia; Chumakova, Katya; Kawamata, Norihiko; Liu, Liqin; Koeffler, H. Phillip

doi:10.1182/blood-2007-05-089326

Cited by 55 publications

(72 citation statements)

References 24 publications

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“…7 LNK has been shown to down regulate signaling downstream of MPLW515L and JAK2V617F in vitro. 8,9 Indeed, in a transduction-transplant murine model, LNK deficiency accelerates and exacerbates MPN development induced by TEL-JAK2 and JAK2V617F. 10 In this model, physical interaction between JAK2V617F and LNK was required for the latter's ability to restrain PV/MF expression; similarly LNK's SH2 domain was required for its ability to restrain TEL-JAK2 induced myeloid expansion in this model.…”

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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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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“…In addition, virtually all of the missense mutations affect highly conserved residues in the PH domain, indicating that plasma membrane localization of LNK may be disrupted (Figure 2c). Previous studies with synthetic LNK mutants have demonstrated that disruption of the PH domain results in loss of LNK inhibitory function [Bersenev et al 2008;Gery et al 2007;Tong and Lodish, 2004]. As most of the LNK mutations identified in MPNs appear to be heterozygous, an important biological question is whether loss of inhibition of JAK-STAT activation is related to haploinsufficiency of LNK or due to dominant negative effects of the mutant protein.…”

Section: Identification Of Novel Lnk Mutations In Mpnsmentioning

confidence: 99%

“…A kinase-inactive mutant of JAK2 results in decreased binding to LNK, suggesting that JAK2 phosphorylates LNK, which may lead to its enhanced binding. Gery and colleagues demonstrated that LNK binds to MPL and colocalizes with MPL at the plasma membrane [Gery et al 2007]. The SH2 domain of LNK is essential for this interaction, as well as for the inhibition of downstream signaling.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the PH domain is required for membrane localization. Interestingly, LNK can bind and inhibit JAK2 V617F as well as MPL W515L [Gery et al 2009[Gery et al , 2007Bersenev et al 2008], suggesting that even in the presence of these activating mutations, additional mechanisms may need to be recruited in order to evade inhibition by LNK. In support of this notion, a recent study demonstrated that in mice expressing activated forms of JAK2 (either JAK2 V617F or the TEL-JAK2 fusion), loss of LNK function accelerates and exacerbates the development of an MPN-like disease [Bersenev et al 2010].…”

Section: Introductionmentioning

confidence: 99%

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When the brakes are lost: LNK dysfunction in mice, men, and myeloproliferative neoplasms

2010

Therapeutic Advances in Hematology

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Aberrant JAK-STAT signaling is a hallmark of myeloproliferative neoplasms (MPNs). These hyperproliferative disorders are classically associated with activating mutations in tyrosine kinases such as JAK2 and the thrombopoietin (TPO) receptor MPL. Activation of JAK-STAT signaling and responses to JAK2 inhibitors have been observed in MPN patients lacking JAK2 or MPL mutations, suggesting that other regulatory elements in the JAK-STAT pathway are altered. However, the molecular basis for this observation has been unclear. Recently, the role of inhibitory regulators of JAK-STAT signaling in MPN pathogenesis has been increasingly recognized. LNK is an adaptor protein that forms a negative feedback loop by binding to MPL and JAK2 and inhibiting downstream STAT activation. Murine models indicate that loss of LNK function can promote the development of a MPN phenotype. Several recent studies have identified novel LNK mutations in MPNs, thus validating this notion in humans. These findings represent a novel genetic paradigm of loss of negative feedback regulation of JAK-STAT activation in MPNs and have implications for the future development of targeted therapies in MPNs.

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“…Indeed, Lnk, through its SH2 domain, negatively modulates MPL, and EPO receptor (EPOR) signalling by attenuating three major signalling pathways: JAK2/STAT, MAPK and Akt (Tong et al, 2005;Tong & Lodish, 2004). Moreover, Lnk is capable of binding and regulating MPL-W515L and JAK2-V617F, the mutated forms expressed in Myeloproliferative Neoplasms [MPN] (Gery et al, 2007(Gery et al, , 2009Bersenev et al, 2008;Baran-Marszak et al, 2010). In addition, Lnk also regulates thrombopoiesis through control of crosstalk between integrin-and TPO-mediated pathways implicated in the megakaryocyte maturation and platelet release process (Takizawa et al, 2008).…”

Section: Signalling Pathways In Haematopoietic Cellsmentioning

confidence: 99%

Negative Regulation of Haematopoiesis: Role of Inhibitory Adaptors

Velázquez¹

2012

Hematology - Science and Practice

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Adaptor protein Lnk negatively regulates the mutant MPL, MPLW515L associated with myeloproliferative disorders

Cited by 55 publications

References 24 publications

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

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

When the brakes are lost: LNK dysfunction in mice, men, and myeloproliferative neoplasms

Negative Regulation of Haematopoiesis: Role of Inhibitory Adaptors

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