The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α-tubulin acetylation
Kindlins are focal adhesion proteins that regulate integrin activation and outside-in signaling. The kindlin family consists of three members, kindlin-1, -2, and -3. Kindlin-2 is widely expressed in multiple cell types, except those from the hematopoietic lineage. A previous study has reported that...
| Main Authors: | , |
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| Format: | Journal Article |
| Language: | English |
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2020
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| Online Access: | https://hdl.handle.net/10356/141977 |
| _version_ | 1811690792258895872 |
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| author | Tan, Hui-Foon Tan, Suet-Mien |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Tan, Hui-Foon Tan, Suet-Mien |
| author_sort | Tan, Hui-Foon |
| collection | NTU |
| description | Kindlins are focal adhesion proteins that regulate integrin activation and outside-in signaling. The kindlin family consists of three members, kindlin-1, -2, and -3. Kindlin-2 is widely expressed in multiple cell types, except those from the hematopoietic lineage. A previous study has reported that the Drosophila Fit1 protein (an ortholog of kindlin-2) prevents abnormal spindle assembly; however, the mechanism remains unknown. Here, we show that kindlin-2 maintains spindle integrity in mitotic human cells. The human neuroblastoma SH-SY5Y cell line expresses only kindlin-2, and we found that when SH-SY5Y cells are depleted of kindlin-2, they exhibit pronounced spindle abnormalities and delayed mitosis. Of note, acetylation of α-tubulin, which maintains microtubule flexibility and stability, was diminished in the kindlin-2–depleted cells. Mechanistically, we found that kindlin-2 maintains α-tubulin acetylation by inhibiting the microtubule-associated deacetylase histone deacetylase 6 (HDAC6) via a signaling pathway involving AKT Ser/Thr kinase (AKT)/glycogen synthase kinase 3 β (GSK3β) or paxillin. We also provide evidence that prolonged hypoxia down-regulates kindlin-2 expression, leading to spindle abnormalities not only in SH-SY5Y cell line but also cell lines derived from colon and breast tissues. The findings of our study highlight that kindlin-2 regulates mitotic spindle assembly and that this process is perturbed in cancer cells in a hypoxic environment. |
| first_indexed | 2024-10-01T06:09:37Z |
| format | Journal Article |
| id | ntu-10356/141977 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:09:37Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1419772023-02-28T17:06:38Z The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α-tubulin acetylation Tan, Hui-Foon Tan, Suet-Mien School of Biological Sciences Science::Biological sciences Adhesion Kindlin Kindlins are focal adhesion proteins that regulate integrin activation and outside-in signaling. The kindlin family consists of three members, kindlin-1, -2, and -3. Kindlin-2 is widely expressed in multiple cell types, except those from the hematopoietic lineage. A previous study has reported that the Drosophila Fit1 protein (an ortholog of kindlin-2) prevents abnormal spindle assembly; however, the mechanism remains unknown. Here, we show that kindlin-2 maintains spindle integrity in mitotic human cells. The human neuroblastoma SH-SY5Y cell line expresses only kindlin-2, and we found that when SH-SY5Y cells are depleted of kindlin-2, they exhibit pronounced spindle abnormalities and delayed mitosis. Of note, acetylation of α-tubulin, which maintains microtubule flexibility and stability, was diminished in the kindlin-2–depleted cells. Mechanistically, we found that kindlin-2 maintains α-tubulin acetylation by inhibiting the microtubule-associated deacetylase histone deacetylase 6 (HDAC6) via a signaling pathway involving AKT Ser/Thr kinase (AKT)/glycogen synthase kinase 3 β (GSK3β) or paxillin. We also provide evidence that prolonged hypoxia down-regulates kindlin-2 expression, leading to spindle abnormalities not only in SH-SY5Y cell line but also cell lines derived from colon and breast tissues. The findings of our study highlight that kindlin-2 regulates mitotic spindle assembly and that this process is perturbed in cancer cells in a hypoxic environment. NRF (Natl Research Foundation, S’pore) MOE (Min. of Education, S’pore) MOH (Min. of Health, S’pore) Accepted version 2020-06-12T08:56:25Z 2020-06-12T08:56:25Z 2020 Journal Article Tan, H.-F., & Tan, S.-M. (2020). The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α-tubulin acetylation. Journal of Biological Chemistry, 295(18), 5928-5943. doi:10.1074/jbc.ra120.012954 0021-9258 https://hdl.handle.net/10356/141977 10.1074/jbc.ra120.012954 18 295 5928 5943 en Journal of Biological Chemistry © 2020 The Author(s). All rights reserved. This paper was published by The American Society for Biochemistry and Molecular Biology, Inc. in Journal of Biological Chemistry and is made available with permission of The Author(s). application/pdf |
| spellingShingle | Science::Biological sciences Adhesion Kindlin Tan, Hui-Foon Tan, Suet-Mien The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α-tubulin acetylation |
| title | The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α-tubulin acetylation |
| title_full | The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α-tubulin acetylation |
| title_fullStr | The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α-tubulin acetylation |
| title_full_unstemmed | The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α-tubulin acetylation |
| title_short | The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α-tubulin acetylation |
| title_sort | focal adhesion protein kindlin 2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α tubulin acetylation |
| topic | Science::Biological sciences Adhesion Kindlin |
| url | https://hdl.handle.net/10356/141977 |
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