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Cell Signalling,Cell Growth & Division,Leukocyte Activation,Immune Response, Autoimmunity
Cyclin dependent kinases (Cdks) are crucial enzymes responsible for directing cell-cycle progression. It is not surprising that the activity of this family of serine/threonine kinases is under intense control, which includes two families of cyclin dependent kinase inhibitors, the Cip/Kip and Ink4 families. Progression from G1 into S phase is controlled by the Cip/Kip family member p27, which inhibits cyclin E/Cdk2 kinase activity until the cell has been induced by external signals to commit to duplication of its complement of DNA. This paper provides compelling results indicating that in both B and T cells this key cell-cycle checkpoint is controlled, at least in part, by Rap1-GTP binding protein (RAPL), a protein previously thought to regulate lymphocyte adhesion through its modulation of the small GTPase Ras-related protein1 (Rap1). First of all, the authors provide experimental results in which both primary B and T cells and cell lines are used. The fact that this checkpoint is confirmed in primary cells is very important.The checkpoint targeted by RAPL modulates this key G1/S checkpoint by controlling the nuclear export of p27, since p27 must be in the nucleus to inhibit cyclin E/Cdk2 activity. G1 localized cells must neutralize p27 to pass the G1 restriction point and enter S phase since a threshold level of cyclin E/Cdk2 activity must be reached prior to the cells acquiring the capability to initiate such S phase events as formation of replication complexes and duplication of centrosomes. The authors show that the role for RAPL in this process is to block the phosphorylation of p27 on serine 10 by controlling kinase-interacting stathmin (KIS), the kinase responsible for this phosphorylation. All p27 proteins phosphorylated on serine 10 are retained within the cytoplasm, so RAPL helps to maintain cyclin E/Cdk2 in the inactive configuration until it is time to release the cells to enter S phase. Mice defective in RAPL are found to suffer from immunoproliferative disease, development of B cell lymphomas and development of lupus-like autoimmune disease. Although many of the findings shown in this paper demonstrate similarities in this mechanism in B and T cells, there are some differences that help explain why B cells are found to be more dysfunctional when RAPL is absent.