Immune Netw.  2009 Apr;9(2):35-40. 10.4110/in.2009.9.2.35.

Rap Signaling in Normal Lymphocyte Development and Leukemia Genesis

• Minato N

• KMID: 1474592
• DOI: http://doi.org/10.4110/in.2009.9.2.35

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.

Keyword

lymphocyte development; leukemia; RapGTPases; Spa-1; Notch

MeSH Terms

Animals
Cell Lineage
Cell Proliferation
GTP Phosphohydrolases
Hand
Humans
Leukemia
Lymphocytes
Mice
GTP Phosphohydrolases

Figure

• 

  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.

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