SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia

Pasmant, Éric; Gilbert‐Dussardier, Brigitte; Petit, Arnaud; Laval, Bérengère de; Luscan, Armelle; Gruber, Aurélia; Lapillonne, Hélène; Deswarte, Caroline; Goussard, P; Laurendeau, Ingrid; Uzan, Benjamin; Pflumio, Françoise; Brizard, Françoise; Vabres, P.; Naguibvena, I; Fasola, Sylvie; Millot, Frédéric; Porteu, Françoise; Vidaud, Dominique; Landman‐Parker, Judith; Ballerini, Paola

doi:10.1038/onc.2013.587

Cited by 42 publications

(43 citation statements)

References 32 publications

(43 reference statements)

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“…[49][50][51][52][53][54][55] Among the 88 miR-126KO1 AE9a_High genes (supplemental Table 5), Fzd7, a Wnt receptor Figure 5. Comparison of expression levels between Pri HSPCs and CPs for the genes dysregulated in AE9a1miR-126 and miR-126KO1AE9a leukemic cells.…”

Section: Overexpression and Knockout Of Mir-126 Trigger Distinct Genementioning

confidence: 99%

Overexpression and knockout of miR-126 both promote leukemogenesis

Chen

et al. 2015

Blood

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Key Points• Both overexpression and knockout of miR-126 result in enhanced leukemogenesis.• Overexpression and knockout of miR-126 activate distinct gene signaling and are associated with different biological consequences.It is generally assumed that gain-and loss-of-function manipulations of a functionally important gene should lead to the opposite phenotypes. We show in this study that both overexpression and knockout of microRNA (miR)-126 surprisingly result in enhanced leukemogenesis in cooperation with the t(8;21) fusion genes AML1-ETO/RUNX1-RUNX1T1 and AML1-ETO9a (a potent oncogenic isoform of AML1-ETO). In accordance with our observation that increased expression of miR-126 is associated with unfavorable survival in patients with t(8;21) acute myeloid leukemia (AML), we show that miR-126 overexpression exhibits a stronger effect on long-term survival and progression of AML1-ETO9a-mediated leukemia stem cells/leukemia initiating cells (LSCs/LICs) in mice than does miR-126 knockout. Furthermore, miR-126 knockout substantially enhances responsiveness of leukemia cells to standard chemotherapy. Mechanistically, miR-126 overexpression activates genes that are highly expressed in LSCs/LICs and/or primitive hematopoietic stem/progenitor cells, likely through targeting ERRFI1 and SPRED1, whereas miR-126 knockout activates genes that are highly expressed in committed, more differentiated hematopoietic progenitor cells, presumably through inducing FZD7 expression. Our data demonstrate that miR-126 plays a critical but 2-faceted role in leukemia and thereby uncover a new layer of miRNA regulation in cancer. Moreover, because miR-126 depletion can sensitize AML cells to standard chemotherapy, our data also suggest that miR-126 represents a promising therapeutic target. (Blood. 2015;126(17):2005-2015 Introduction MicroRNAs (miRNAs) have been implicated in the pathogenesis of various types of cancers. [1][2][3][4][5][6][7][8] Some miRNAs play distinct roles in different types of cancers. For example, miRNA (miR)-126, originally identified as an endothelial-specific miRNA playing an essential role in angiogenesis and vascular integrity, [9][10][11] has been shown to function as a critical tumor suppressor in various types of solid tumors. 5,[12][13][14][15][16][17][18][19] In contrast, we have shown that miR-126 is aberrantly overexpressed and likely plays an oncogenic role in core binding factor (CBF) leukemia. 20 CBF leukemia is characterized by the presence of a t(8;21)(q22;q22) or an inv(16)(p13.1q22) chromosomal rearrangement, which accounts for ;20% to 30% of primary acute myeloid leukemia (AML) cases. [21][22][23] The potential oncogenic role of miR-126 in AML was further confirmed by other groups. 24,25 However, it was reported that attenuation of miR-126 expression in normal hematopoietic stem/progenitor cells (HSPCs) resulted in expansion of long-term repopulating hematopoietic stem cells. 26 Thus, the definitive role of miR-126 in the hematopoietic system warrants further investigation.To precisely define ...

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Section: Overexpression and Knockout Of Mir-126 Trigger Distinct Genementioning

confidence: 99%

Overexpression and knockout of miR-126 both promote leukemogenesis

Chen

et al. 2015

Blood

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“…Furthermore, Spreds are putative tumor suppressors. It has been reported that SPRED1 and SPRED2 expression is reduced in human hepatocellular carcinoma (14), and SPRED1 mutation and reduced expression are also found in acute myeloblastic leukemia (12). Overexpression of SPRD1 in tumor cells resulted in reduced tumorigenicity in nude mice (15).…”

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confidence: 99%

“…The phenotype exhibited by such patients is known as NF1-like syndrome or Legius syndrome (OMIM 611431) and consists of multiple café-au-lait macules (CALM), axillary freckling, macrocephaly, and sometimes mild neurocognitive impairment, as well as a lack of certain features that are common in NF1, such as neurofibromas, iris Lisch nodules, and NF1-related malignancies (11). However, there might be an increased risk for leukemia in children with Legius syndrome (12). The similarities between NF1 and Legius syndrome, as well as that between the biochemical functions of neurofibromin and those of SPRED1, suggest that these two syndromes both result in part from hyperactive Ras-ERK signaling, as are Noonan syndrome, Noonan syndrome with lentigines (previ-ous LEOPARD syndrome), cardio-facio-cutaneous syndrome, and Costello syndrome (13).…”

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confidence: 99%

Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1

Hirata

Brems

Suzuki

et al. 2016

Journal of Biological Chemistry

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Constitutional heterozygous loss-of-function mutations in the SPRED1 gene cause a phenotype known as Legius syndrome, which consists of symptoms of multiple café-au-lait macules, axillary freckling, learning disabilities, and macrocephaly. Legius syndrome resembles a mild neurofibromatosis type 1 (NF1) phenotype. It has been demonstrated that SPRED1 functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product. However, the molecular details of this interaction and the effects of the mutations identified in Legius syndrome and NF1 on this interaction have not yet been investigated. In this study, using a yeast two-hybrid system and an immunoprecipitation assay in HEK293 cells, we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin, which form two crossing ␣-helix coils outside the GAP domain. These regions have been shown to be dispensable for GAP activity and are not present in p120 GAP . Several mutations in these N-and C-terminal regions of the GRD in NF1 patients and pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius syndrome reduced the binding affinity between the EVH1 domain and the GRD. EVH1 domain mutations with reduced binding to the GRD also disrupted the ERK suppression activity of SPRED1. These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway by recruiting neurofibromin to Ras through the EVH1-GRD interaction, and this study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome.Spred (Sprouty-related protein with an EVH1 domain) family proteins, initially discovered as c-Kit-and c-Fms-binding proteins, have been shown to suppress the Ras-ERK pathway. Spreds form a subfamily of the Sprouty/Spred family, which is characterized by the Sprouty-related C-terminal cysteine-rich (SPR) 3 domain. In mammals, four Sprouty homologues and three members of the Spred family of proteins, Spred1, Spred2, and Spred3, have been discovered. Mammalian Spreds can negatively regulate the Ras-Raf-ERK pathway (1, 2); however, compared with Spred1 and Spred2, Spred3 has much weaker ERK suppression activity (3). The SPR domain has been shown to be palmitoylated, causing Sprouty and Spred to localize in the membrane fraction (4, 5). Spred1 and Spred2 are composed of an N-terminal enabled/vasodilator-stimulated protein homology 1 (EVH1) domain, a central c-Kit-binding domain, and a cysteine-rich C-terminal SPR domain, whereas Spred3 lacks a functional c-Kit-binding domain.

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“…LS is caused by germ-line mutations in the SPRED1 gene (17,18) encoding the Sprouty-related, EVH1 domain-containing protein 1 (Spred1), which has been demonstrated to specifically inhibit the Ras/MAPK pathway in response to growth factor-, cytokine-, and chemokine-induced ERK activation (19)(20)(21)(22). In pediatric acute myeloblastic leukemia, Spred1 acts as a tumor suppressor (23). The 50-kDa protein comprises an N-terminal Ena/VASP Homology 1 (EVH1) domain (24) and a C-terminal Sprouty-related domain (SPR) separated by a central c-Kit binding domain (19).…”

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The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation

Dunzendorfer-Matt

Mercado

Maly

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Neurofibromatosis type 1 (NF1) and Legius syndrome are related diseases with partially overlapping symptoms caused by alterations of the tumor suppressor genes NF1 (encoding the protein neurofibromin) and SPRED1 (encoding sprouty-related, EVH1 domain-containing protein 1, Spred1), respectively. Both proteins are negative regulators of Ras/MAPK signaling with neurofibromin functioning as a Rasspecific GTPase activating protein (GAP) and Spred1 acting on hitherto undefined components of the pathway. Importantly, neurofibromin has been identified as a key protein in the development of cancer, as it is genetically altered in a large number of sporadic human malignancies unrelated to NF1. Spred1 has previously been demonstrated to interact with neurofibromin via its N-terminal Ena/VASP Homology 1 (EVH1) domain and to mediate membrane translocation of its target dependent on its C-terminal Sprouty domain. However, the region of neurofibromin required for the interaction with Spred1 has remained unclear. Here we show that the EVH1 domain of Spred1 binds to the noncatalytic (GAPex) portion of the GAP-related domain (GRD) of neurofibromin. Binding is compatible with simultaneous binding of Ras and does not interfere with GAP activity. Our study points to a potential targeting function of the GAPex subdomain of neurofibromin that is present in all known canonical RasGAPs.cancer | signal transduction | protein-protein interaction | RASopathy | nontruncating mutations

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SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia

Cited by 42 publications

References 32 publications

Overexpression and knockout of miR-126 both promote leukemogenesis

Overexpression and knockout of miR-126 both promote leukemogenesis

Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1

The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation

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