Evaluation
details:
Must
Read [8]
Sections:
Cell
Signalling,Cell Growth & Division,Leukocyte Activation,Immune Response,
Autoimmunity
Comments:
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.