Cargando…
Cyclin-Dependent Kinase 5 Promotes Pancreatic β-Cell Survival via Fak-Akt Signaling Pathways
OBJECTIVE: Cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 has recently been linked to type 2 diabetes by genome-wide association studies. While CDK5 and its regulatory protein p35 are both expressed and display enzymatic activity in pancreatic β-cells, their precise...
Autores principales: | , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2011
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064092/ https://www.ncbi.nlm.nih.gov/pubmed/21378178 http://dx.doi.org/10.2337/db10-1048 |
_version_ | 1782200874076995584 |
---|---|
author | Daval, Marie Gurlo, Tatyana Costes, Safia Huang, Chang-jiang Butler, Peter C. |
author_facet | Daval, Marie Gurlo, Tatyana Costes, Safia Huang, Chang-jiang Butler, Peter C. |
author_sort | Daval, Marie |
collection | PubMed |
description | OBJECTIVE: Cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 has recently been linked to type 2 diabetes by genome-wide association studies. While CDK5 and its regulatory protein p35 are both expressed and display enzymatic activity in pancreatic β-cells, their precise role in the β-cell remains unknown. Because type 2 diabetes is characterized by a deficit in β-cell mass and increased β-cell apoptosis, we investigated the role of CDK5 in β-cell survival. RESEARCH DESIGN AND METHODS: We used INS 832/13 cells, rat islets isolated from wild-type or human islet amyloid polypeptide (h-IAPP) transgenic rats, and pancreatic tissue from rats and humans with and without type 2 diabetes and investigated the effect of CDK5/p35 inhibition (by small interfering RNA or by chemical inhibition) as well as CDK5/p35 overexpression on β-cell vulnerability to apoptosis. RESULTS: CDK5 inhibition led to increased β-cell apoptosis. To identify the mechanisms involved, we examined the phosphorylation state of focal adhesion kinase (Fak)(Ser732), a known target of CDK5. Following CDK5 inhibition, the phosphorylation of Fak(Ser732) decreased with resulting attenuation of phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway. Conversely, CDK5 overexpression increased Fak(Ser732) phosphorylation and protected β-cells against apoptosis induced by the inhibition of the β-1 integrin signaling pathway. Also, Fak(Ser732) phosphorylation was less abundant in β-cells in both h-IAPP transgenic rats and humans with type 2 diabetes. CONCLUSIONS: This study shows that by regulating Fak phosphorylation and subsequently PI3K/Akt survival pathway, CDK5 plays a previously unrecognized role in promoting β-cell survival. |
format | Text |
id | pubmed-3064092 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-30640922012-04-01 Cyclin-Dependent Kinase 5 Promotes Pancreatic β-Cell Survival via Fak-Akt Signaling Pathways Daval, Marie Gurlo, Tatyana Costes, Safia Huang, Chang-jiang Butler, Peter C. Diabetes Islet Studies OBJECTIVE: Cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 has recently been linked to type 2 diabetes by genome-wide association studies. While CDK5 and its regulatory protein p35 are both expressed and display enzymatic activity in pancreatic β-cells, their precise role in the β-cell remains unknown. Because type 2 diabetes is characterized by a deficit in β-cell mass and increased β-cell apoptosis, we investigated the role of CDK5 in β-cell survival. RESEARCH DESIGN AND METHODS: We used INS 832/13 cells, rat islets isolated from wild-type or human islet amyloid polypeptide (h-IAPP) transgenic rats, and pancreatic tissue from rats and humans with and without type 2 diabetes and investigated the effect of CDK5/p35 inhibition (by small interfering RNA or by chemical inhibition) as well as CDK5/p35 overexpression on β-cell vulnerability to apoptosis. RESULTS: CDK5 inhibition led to increased β-cell apoptosis. To identify the mechanisms involved, we examined the phosphorylation state of focal adhesion kinase (Fak)(Ser732), a known target of CDK5. Following CDK5 inhibition, the phosphorylation of Fak(Ser732) decreased with resulting attenuation of phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway. Conversely, CDK5 overexpression increased Fak(Ser732) phosphorylation and protected β-cells against apoptosis induced by the inhibition of the β-1 integrin signaling pathway. Also, Fak(Ser732) phosphorylation was less abundant in β-cells in both h-IAPP transgenic rats and humans with type 2 diabetes. CONCLUSIONS: This study shows that by regulating Fak phosphorylation and subsequently PI3K/Akt survival pathway, CDK5 plays a previously unrecognized role in promoting β-cell survival. American Diabetes Association 2011-04 2011-03-22 /pmc/articles/PMC3064092/ /pubmed/21378178 http://dx.doi.org/10.2337/db10-1048 Text en © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Islet Studies Daval, Marie Gurlo, Tatyana Costes, Safia Huang, Chang-jiang Butler, Peter C. Cyclin-Dependent Kinase 5 Promotes Pancreatic β-Cell Survival via Fak-Akt Signaling Pathways |
title | Cyclin-Dependent Kinase 5 Promotes Pancreatic β-Cell Survival via Fak-Akt Signaling Pathways |
title_full | Cyclin-Dependent Kinase 5 Promotes Pancreatic β-Cell Survival via Fak-Akt Signaling Pathways |
title_fullStr | Cyclin-Dependent Kinase 5 Promotes Pancreatic β-Cell Survival via Fak-Akt Signaling Pathways |
title_full_unstemmed | Cyclin-Dependent Kinase 5 Promotes Pancreatic β-Cell Survival via Fak-Akt Signaling Pathways |
title_short | Cyclin-Dependent Kinase 5 Promotes Pancreatic β-Cell Survival via Fak-Akt Signaling Pathways |
title_sort | cyclin-dependent kinase 5 promotes pancreatic β-cell survival via fak-akt signaling pathways |
topic | Islet Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064092/ https://www.ncbi.nlm.nih.gov/pubmed/21378178 http://dx.doi.org/10.2337/db10-1048 |
work_keys_str_mv | AT davalmarie cyclindependentkinase5promotespancreaticbcellsurvivalviafakaktsignalingpathways AT gurlotatyana cyclindependentkinase5promotespancreaticbcellsurvivalviafakaktsignalingpathways AT costessafia cyclindependentkinase5promotespancreaticbcellsurvivalviafakaktsignalingpathways AT huangchangjiang cyclindependentkinase5promotespancreaticbcellsurvivalviafakaktsignalingpathways AT butlerpeterc cyclindependentkinase5promotespancreaticbcellsurvivalviafakaktsignalingpathways |