Lyn contributes to regulation of multiple Kit-dependent signaling pathways in murine bone marrow mast cells

Shivakrupa, R.; Linnekin, Diana

doi:10.1016/j.cellsig.2004.06.004

Cited by 41 publications

(34 citation statements)

References 46 publications

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“…The expression of basal markers at low levels in the normal c-Kit þ luminal progenitors (Table 1) and the presence in the tumours of neoplastic cells with both luminal and basal features, would be consistent with such a block. Lyn is a potential regulator of Brca1, acting via Akt Altiok et al, 1999;Shivakrupa and Linnekin, 2005). Brca1 is itself a potential regulator of Lyn, acting via CDC2 (Pathan et al, 1996;Wang et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

et al. 2011

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BRCA1 mutation-associated breast cancer originates in oestrogen receptor-alpha-negative (ER À ) progenitors in the mammary luminal epithelium. These cells also express high levels of the Kit gene and a recent study demonstrated a correlation between Brca1 loss and Kit over-expression in the mammary epithelium. However, the functional significance of c-Kit expression in the mammary gland is unknown. To address this, c-Kit À and c-Kit þ mammary epithelial subsets were isolated by flow cytometry, characterised for expression of lineage-specific cell markers and functionally analysed by in vitro colony forming and in vivo transplantation assays. The results confirm that the majority of luminal ER À progenitors are c-Kit þ , but also that most stem cells and the differentiated cell populations are c-Kit À . A subset of c-Kit þ cells with high proliferative potential was found in the luminal ER þ population, however, suggesting the existence of a distinct luminal ER þ progenitor cell type. Analysis of mouse Brca1 mammary tumours demonstrated that they expressed Kit and its downstream effector Lyn at levels comparable to the most strongly c-Kit þ luminal ER À progenitors. Consistent with c-Kit being a progenitor cell marker, in vitro threedimensional differentiation of c-Kit þ cells resulted in a loss of c-Kit expression, whereas c-Kit over-expression prevented normal differentiation in vivo. Furthermore, c-Kit was a functional marker of proliferative potential, as c-Kit inhibition by short hairpin knockdown prevented normal epithelial growth and caused cells to undergo apoptosis. Therefore, c-Kit defines distinct progenitor populations in the mammary epithelium and is critical for mammary progenitor survival and proliferation. Importantly, c-Kit is only the second mammary epithelial stem/progenitor marker to be shown to have a functional role in the mammary epithelium and the first marker to be shown to be required for progenitor cell function. The c-Kit signalling network has potential as a target for therapy and/or prevention in BRCA1-associated breast cancer.

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Section: Discussionmentioning

confidence: 99%

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

et al. 2011

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“…Binding of either Lyn or Fyn to Y567/Y569 in Kit results in regulation of several signaling pathways in mast cells, which are implicated in SCF-dependent proliferation and chemotaxis. [47][48][49] In contrast, Fyn promotes phosphorylation of Shp2 and activation of p38 MAPK and is also essential for chemotaxis. 32 The importance of Src pathways was further underscored by a study using several c-Kit mutant receptors to analyze single biochemical pathways elicited by this receptor.…”

Section: Discussionmentioning

confidence: 99%

Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells

Simon

Dondi

Chaix

et al. 2008

Blood

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IntroductionMast cells are multifunctional hematopoietic cells, important for both innate and specific immunity. 1 Immature mast cells leave the bone marrow to migrate to target tissues, mostly mucosal and connective tissues, where they undergo terminal differentiation and perform their biologic functions. 2 Stem cell factor (SCF) and its receptor Kit are essential for mast cell development in vivo, as shown by the phenotype of mice with null mutations in the Kit (White Spotting or W) or SCF (Steel or Sl) loci. Indeed, these mice lack tissue mast cells and also exhibit defects in hematopoiesis, pigmentation, and reproduction. 3 In bone marrow mast cells (BMMCs), activation of Kit, a type III receptor tyrosine kinase (RTK), stimulates cellular responses such as proliferation, survival, differentiation, chemotaxis, cell adhesion, and degranulation. 4 Upon SCF binding, the Kit receptor dimerizes, autophosphorylates, and subsequently transphosphorylates specific tyrosines (Y). The resulting phosphotyrosine (pY) residues serve as docking sites for Src homology 2 (SH2) domain-containing proteins, which control intracellular signaling pathways such as all 3 mitogen-activated protein kinases (MAPKs; ERK, p38, and c-jun N-terminal kinase [JNK]), phosphatidylinositol 3-kinase (PI-3K), and Janus kinases (JAK)/signal transducers and activators of transcription (STAT) pathways. 4,5 Recruitment of particular targets is mediated by the ability of SH2 domains to recognize specific pY-containing motifs on the activated receptor. Analyses of individual docking sites on Kit have provided valuable information about the activation of pathways emanating from this receptor. 6 Juxtamembrane Y567 and Y569 are critical recruitment sites for different regulatory signaling molecules. These include activators such as Src family kinases (Fyn and Lyn), Shp-2 phosphatase and Shc adaptor protein, or negative modulators such as Shp-1 phosphatase, Csk-homology kinase (Chk), suppressors of cytokine signaling (SOCS) proteins, and APS adaptor protein. 5,7,8 Mutational and "knock-in" studies on Kit Y567/Y569 have revealed their important role in cell development, proliferation, survival, and migration. 6,9-11 However, the biologic significance of these interactions is still poorly understood.Lnk is a member of the adaptor protein family that includes APS and SH2-B. All 3 members share common protein-protein interaction domains and motifs: a dimerization domain at the aminoterminus, a pleckstrin homology (PH) domain, an SH2 domain, and a conserved tyrosine near the carboxy-terminus. 12 Mice deficient for members of this family have demonstrated the positive (SH2-B) and negative (Lnk and APS) role of these adaptors in growth factor, cytokine, and antigen-receptor signaling. [13][14][15][16][17][18] In particular, Lnk nullizygous mice show mainly a profound perturbation in hematopoiesis. These animals exhibit splenomegaly together with fibrosis, expansion of hematopoietic stem cells (HSCs), and myeloid and B lymphoid progenitors. [17][18][19] Recent ana...

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“…Moreover, KIT D816V did not cause activation of Lyn or Btk in Ba/F3 cells, which was an unexpected result when considering previous data. [43][44][45] However, in previous studies, Mo7e cells and murine BM MCs were used. [43][44][45] We next were interested to learn whether Lyn and Btk contribute to abnormal growth and survival of neoplastic MCs.…”

Section: Discussionmentioning

confidence: 99%

KIT-D816V–independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk activation and disruption by dasatinib and bosutinib

Gleixner¹,

Mayerhofer

Cerny-Reiterer³

et al. 2011

Blood

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Lyn contributes to regulation of multiple Kit-dependent signaling pathways in murine bone marrow mast cells

Cited by 41 publications

References 46 publications

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells

KIT-D816V–independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk activation and disruption by dasatinib and bosutinib

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