Abstract
RAPL (an alternative spliced form of Rassf5) is a critical Ras-related protein1 (Rap1) effector that regulates lymphocyte adhesion. Here, we have shown that in addition to this previously described function, RAPL also negatively controls lymphocyte proliferation and prevents autoimmunity and lymphoma. RAPL-deficient mice experienced age-related lupus-like glomerulonephritis and developed B cell lymphomas. RAPL-deficient lymphocytes showed hyperproliferation by enhanced S phase entry after antigen receptor ligation. Compared to wild-type cells, RAPL-deficient naive lymphocytes had a 2- to 3-fold increase in Cdk2 kinase activity with a cytoplasmic mislocalization of the cyclin-dependent kinase inhibitor p27kip1. RAPL was found to suppress the phosphorylation of p27kip1 on serine 10 (S10) and promoted p27kip1 nuclear translocation. An S10A mutation in p27kip1 corrected its cytoplasmic accumulation, reduced hyperproliferation in RAPL-deficient lymphocytes, and suppressed glomerulonephritis and development of B cell lymphoma. Thus, RAPL serves as a checkpoint for S phase entry to prevent lymphoproliferative disorders through the spatial regulation of p27kip1.
| Original language | English |
|---|---|
| Pages (from-to) | 24-38 |
| Number of pages | 15 |
| Journal | Immunity |
| Volume | 34 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 28 2011 |
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All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Immunology
- Infectious Diseases
Cite this
Deficiency of Rap1-Binding Protein RAPL Causes Lymphoproliferative Disorders through Mislocalization of p27kip1. / Katagiri, Koko; Ueda, Yoshihiro; Tomiyama, Takashi; Yasuda, Kaneki; Toda, Yoshinobu; Ikehara, Susumu; Nakayama, Keiichi; Kinashi, Tatsuo.
In: Immunity, Vol. 34, No. 1, 28.01.2011, p. 24-38.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Deficiency of Rap1-Binding Protein RAPL Causes Lymphoproliferative Disorders through Mislocalization of p27kip1
AU - Katagiri, Koko
AU - Ueda, Yoshihiro
AU - Tomiyama, Takashi
AU - Yasuda, Kaneki
AU - Toda, Yoshinobu
AU - Ikehara, Susumu
AU - Nakayama, Keiichi
AU - Kinashi, Tatsuo
PY - 2011/1/28
Y1 - 2011/1/28
N2 - RAPL (an alternative spliced form of Rassf5) is a critical Ras-related protein1 (Rap1) effector that regulates lymphocyte adhesion. Here, we have shown that in addition to this previously described function, RAPL also negatively controls lymphocyte proliferation and prevents autoimmunity and lymphoma. RAPL-deficient mice experienced age-related lupus-like glomerulonephritis and developed B cell lymphomas. RAPL-deficient lymphocytes showed hyperproliferation by enhanced S phase entry after antigen receptor ligation. Compared to wild-type cells, RAPL-deficient naive lymphocytes had a 2- to 3-fold increase in Cdk2 kinase activity with a cytoplasmic mislocalization of the cyclin-dependent kinase inhibitor p27kip1. RAPL was found to suppress the phosphorylation of p27kip1 on serine 10 (S10) and promoted p27kip1 nuclear translocation. An S10A mutation in p27kip1 corrected its cytoplasmic accumulation, reduced hyperproliferation in RAPL-deficient lymphocytes, and suppressed glomerulonephritis and development of B cell lymphoma. Thus, RAPL serves as a checkpoint for S phase entry to prevent lymphoproliferative disorders through the spatial regulation of p27kip1.
AB - RAPL (an alternative spliced form of Rassf5) is a critical Ras-related protein1 (Rap1) effector that regulates lymphocyte adhesion. Here, we have shown that in addition to this previously described function, RAPL also negatively controls lymphocyte proliferation and prevents autoimmunity and lymphoma. RAPL-deficient mice experienced age-related lupus-like glomerulonephritis and developed B cell lymphomas. RAPL-deficient lymphocytes showed hyperproliferation by enhanced S phase entry after antigen receptor ligation. Compared to wild-type cells, RAPL-deficient naive lymphocytes had a 2- to 3-fold increase in Cdk2 kinase activity with a cytoplasmic mislocalization of the cyclin-dependent kinase inhibitor p27kip1. RAPL was found to suppress the phosphorylation of p27kip1 on serine 10 (S10) and promoted p27kip1 nuclear translocation. An S10A mutation in p27kip1 corrected its cytoplasmic accumulation, reduced hyperproliferation in RAPL-deficient lymphocytes, and suppressed glomerulonephritis and development of B cell lymphoma. Thus, RAPL serves as a checkpoint for S phase entry to prevent lymphoproliferative disorders through the spatial regulation of p27kip1.
UR - http://www.scopus.com/inward/record.url?scp=78751704150&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78751704150&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2010.12.010
DO - 10.1016/j.immuni.2010.12.010
M3 - Article
C2 - 21194982
AN - SCOPUS:78751704150
VL - 34
SP - 24
EP - 38
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 1
ER -