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Rap signaling in normal lymphocyte development and leukemia genesis.

Minato N - Immune Netw (2009)

Bottom Line: With the use of gene-engineered mice, we have uncovered essential roles of endogenous Rap signaling in normal lymphocyte development of both T- and B-lineage cells.Deregulation of Rap signaling, on the other hand, results in the development of characteristic leukemia in manners highly dependent on the contexts of cell lineages.These results highlight crucial roles of Rap signaling in the physiology and pathology of lymphocyte development.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.

ABSTRACT
Although Rap GTPases of the Ras family remained enigmatic for years, extensive studies in this decade have revealed diverse functions of Rap signaling in the control of cell proliferation, differentiation, survival, adhesion, and movement. With the use of gene-engineered mice, we have uncovered essential roles of endogenous Rap signaling in normal lymphocyte development of both T- and B-lineage cells. Deregulation of Rap signaling, on the other hand, results in the development of characteristic leukemia in manners highly dependent on the contexts of cell lineages. These results highlight crucial roles of Rap signaling in the physiology and pathology of lymphocyte development.

No MeSH data available.


Related in: MedlinePlus

Rap signaling plays essential roles in normal lymphocyte development and leukemia genesis. Endogenous Rap signaling in T- and B-lineage cells has been conditionally modified by genetic manipulations; it is inhibited by the transgenic expression of SPA-1 or Rap1A17 (blue), and augmented by SPA-1 KO or C3G-F expression (red). Rap activation downstream of pre- TCR signaling is crucial to rescue the thymic pre-T cells with proper expression of TCRβ chains from p53-dependent cell death, called β-selection checkpoint. On the contrary, constitutive Rap activation in T-lineage progenitors results in the Notch-mutations and Notch-dependent T-ALL genesis. Rap signaling is also essential for the competence of IL-7-mediated survival and proliferation of pre-B cells in the BM. In addition, Rap signaling functions as a "self-sensing signal" in the immature B cells of BM to initiate B cell receptor (BCR) editing. The deregulated activation of Rap results in the acute B-CLL in collaboration with the loss-of function of p53 or B1-CLL associated with autoantibodies.
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Figure 1: Rap signaling plays essential roles in normal lymphocyte development and leukemia genesis. Endogenous Rap signaling in T- and B-lineage cells has been conditionally modified by genetic manipulations; it is inhibited by the transgenic expression of SPA-1 or Rap1A17 (blue), and augmented by SPA-1 KO or C3G-F expression (red). Rap activation downstream of pre- TCR signaling is crucial to rescue the thymic pre-T cells with proper expression of TCRβ chains from p53-dependent cell death, called β-selection checkpoint. On the contrary, constitutive Rap activation in T-lineage progenitors results in the Notch-mutations and Notch-dependent T-ALL genesis. Rap signaling is also essential for the competence of IL-7-mediated survival and proliferation of pre-B cells in the BM. In addition, Rap signaling functions as a "self-sensing signal" in the immature B cells of BM to initiate B cell receptor (BCR) editing. The deregulated activation of Rap results in the acute B-CLL in collaboration with the loss-of function of p53 or B1-CLL associated with autoantibodies.

Mentions: Conditional expression of Spa-1 in T-lineage cells (lck-Spa-1 Tg mice) resulted in a profound defect of thymic αβ T cell development without affecting γδ T cells (13). The thymic CD4/CD8 double-positive (DP) T cells were markedly diminished due to the arrested transition from double-negative (DN) stage 3 (CD25+ CD44-) to DN stage 4 (CD25- CD44-), corresponding to β-selection checkpoint. In β-selection checkpoint, the thymocytes that have successfully rearranged TCRβ genes and expressed pre-TCR are rescued from cell death followed by the robust expansion via Notch-signaling, whereas those that have failed to do so are doomed to die via p53-dependent pathway (14,15). DN stage 4 thymocytes in the lck-Spa-1 Tg mice revealed a markedly enhanced apoptosis in situ, suggesting that Rap signaling was crucial for the rescue of pre-T cells from cell death. Indeed, it was confirmed that the ligand-independent, autonomous pre-TCR signaling activated both Rap1 and Rap2 in a DN thymocyte cell line. Furthermore, forced expression of farnesylated, constitutive active C3G (C3G-F) in Rag2-/- thymocytes induced their significant expansion in the presence of Notch-ligand (Delta-like 1)-expressing stroma cells, bypassing pre-TCR. And finally, it was found that lck-Spa-1 Tg mice at the p53-/- genetic background showed completely normal development of αβ T cells; the effect of p53 was gene dosage-dependent in that lck-Spa-1 p53+/- mice revealed a partial restoration of DP thymocyte development. These results unambiguously indicate that Rap signaling is essential in the rescue of pre-T cells from p53-mediated cell death in β-selection checkpoint. Currently, it remains unknown how the p53 checkpoint pathway usually associated with DNA damages is activated during pre-T cell development, and it also remains to be investigated how Rap signaling downstream of pre-TCR interferes with the p53-mediated cell death. We have confirmed that essentially identical phenotypes are found in lck-Rap1A17 Tg mice (Wakae, K and Minato, N, unpublished observation). Importantly, CD4-Spa-1 Tg mice showed normal αβ T cell development, indicating that Rap signaling is dispensable for αβ TCR-mediated positive selection (Fig. 1).


Rap signaling in normal lymphocyte development and leukemia genesis.

Minato N - Immune Netw (2009)

Rap signaling plays essential roles in normal lymphocyte development and leukemia genesis. Endogenous Rap signaling in T- and B-lineage cells has been conditionally modified by genetic manipulations; it is inhibited by the transgenic expression of SPA-1 or Rap1A17 (blue), and augmented by SPA-1 KO or C3G-F expression (red). Rap activation downstream of pre- TCR signaling is crucial to rescue the thymic pre-T cells with proper expression of TCRβ chains from p53-dependent cell death, called β-selection checkpoint. On the contrary, constitutive Rap activation in T-lineage progenitors results in the Notch-mutations and Notch-dependent T-ALL genesis. Rap signaling is also essential for the competence of IL-7-mediated survival and proliferation of pre-B cells in the BM. In addition, Rap signaling functions as a "self-sensing signal" in the immature B cells of BM to initiate B cell receptor (BCR) editing. The deregulated activation of Rap results in the acute B-CLL in collaboration with the loss-of function of p53 or B1-CLL associated with autoantibodies.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2803306&req=5

Figure 1: Rap signaling plays essential roles in normal lymphocyte development and leukemia genesis. Endogenous Rap signaling in T- and B-lineage cells has been conditionally modified by genetic manipulations; it is inhibited by the transgenic expression of SPA-1 or Rap1A17 (blue), and augmented by SPA-1 KO or C3G-F expression (red). Rap activation downstream of pre- TCR signaling is crucial to rescue the thymic pre-T cells with proper expression of TCRβ chains from p53-dependent cell death, called β-selection checkpoint. On the contrary, constitutive Rap activation in T-lineage progenitors results in the Notch-mutations and Notch-dependent T-ALL genesis. Rap signaling is also essential for the competence of IL-7-mediated survival and proliferation of pre-B cells in the BM. In addition, Rap signaling functions as a "self-sensing signal" in the immature B cells of BM to initiate B cell receptor (BCR) editing. The deregulated activation of Rap results in the acute B-CLL in collaboration with the loss-of function of p53 or B1-CLL associated with autoantibodies.
Mentions: Conditional expression of Spa-1 in T-lineage cells (lck-Spa-1 Tg mice) resulted in a profound defect of thymic αβ T cell development without affecting γδ T cells (13). The thymic CD4/CD8 double-positive (DP) T cells were markedly diminished due to the arrested transition from double-negative (DN) stage 3 (CD25+ CD44-) to DN stage 4 (CD25- CD44-), corresponding to β-selection checkpoint. In β-selection checkpoint, the thymocytes that have successfully rearranged TCRβ genes and expressed pre-TCR are rescued from cell death followed by the robust expansion via Notch-signaling, whereas those that have failed to do so are doomed to die via p53-dependent pathway (14,15). DN stage 4 thymocytes in the lck-Spa-1 Tg mice revealed a markedly enhanced apoptosis in situ, suggesting that Rap signaling was crucial for the rescue of pre-T cells from cell death. Indeed, it was confirmed that the ligand-independent, autonomous pre-TCR signaling activated both Rap1 and Rap2 in a DN thymocyte cell line. Furthermore, forced expression of farnesylated, constitutive active C3G (C3G-F) in Rag2-/- thymocytes induced their significant expansion in the presence of Notch-ligand (Delta-like 1)-expressing stroma cells, bypassing pre-TCR. And finally, it was found that lck-Spa-1 Tg mice at the p53-/- genetic background showed completely normal development of αβ T cells; the effect of p53 was gene dosage-dependent in that lck-Spa-1 p53+/- mice revealed a partial restoration of DP thymocyte development. These results unambiguously indicate that Rap signaling is essential in the rescue of pre-T cells from p53-mediated cell death in β-selection checkpoint. Currently, it remains unknown how the p53 checkpoint pathway usually associated with DNA damages is activated during pre-T cell development, and it also remains to be investigated how Rap signaling downstream of pre-TCR interferes with the p53-mediated cell death. We have confirmed that essentially identical phenotypes are found in lck-Rap1A17 Tg mice (Wakae, K and Minato, N, unpublished observation). Importantly, CD4-Spa-1 Tg mice showed normal αβ T cell development, indicating that Rap signaling is dispensable for αβ TCR-mediated positive selection (Fig. 1).

Bottom Line: With the use of gene-engineered mice, we have uncovered essential roles of endogenous Rap signaling in normal lymphocyte development of both T- and B-lineage cells.Deregulation of Rap signaling, on the other hand, results in the development of characteristic leukemia in manners highly dependent on the contexts of cell lineages.These results highlight crucial roles of Rap signaling in the physiology and pathology of lymphocyte development.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.

ABSTRACT
Although Rap GTPases of the Ras family remained enigmatic for years, extensive studies in this decade have revealed diverse functions of Rap signaling in the control of cell proliferation, differentiation, survival, adhesion, and movement. With the use of gene-engineered mice, we have uncovered essential roles of endogenous Rap signaling in normal lymphocyte development of both T- and B-lineage cells. Deregulation of Rap signaling, on the other hand, results in the development of characteristic leukemia in manners highly dependent on the contexts of cell lineages. These results highlight crucial roles of Rap signaling in the physiology and pathology of lymphocyte development.

No MeSH data available.


Related in: MedlinePlus